Protein & Cell

, Volume 8, Issue 6, pp 401–438 | Cite as

Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

Open Access
Resource

ABSTRACT

Voltage-gated sodium (Nav) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Cav) channel Cav1.1 provides a template for homology-based structural modeling of the evolutionarily related Nav channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nav1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nav channels, the analysis presented here serves as the base framework for mechanistic investigation of Nav channelopathies and for potential structure-based drug discovery.

Keywords

Nav channels channelopathy Nav1.7 structure modeling pain 

INTRODUCTION

Voltage-gated sodium (Nav) channels are essential for the rapid depolarization phase of action potential and play a key role in the electrical signaling in most excitable cells. Structurally, Nav channels are composed of one α subunit and one or more β subunits. The α subunit contains two functionally distinct structural entities, namely, the voltage-sensing domains (VSDs) and the ion-conducting pore domain (Catterall, 2012b, 2014). The β subunits, which bind to α subunit covalently or non-covalently, modulate membrane trafficking, voltage dependence, and channel gating kinetics (Catterall, 2012b, 2014). In mammals, Nav channels have nine known α members distributed in different excitable tissues. Specifically, Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are the primary sodium channels in central nervous system (CNS), Nav1.4 is primarily expressed in skeletal muscle, Nav1.5 is mainly expressed in heart, and Nav1.7, Nav1.8, and Nav1.9 are mainly distributed in peripheral nervous system (Plummer and Meisler, 1999; Goldin, 2001; Catterall et al., 2005).

All α subunits share nearly identical structure topology—a canonical voltage-gated ion channel fold with four homologous repeats, each containing six transmembrane segments S1–S6. Specifically, S5–S6 segments form the pore domain that conducts selective sodium filtering, while S1–S4 segments constitute the voltage-sensing domain that controls voltage-dependent gating (Catterall, 2000). The voltage sensors in the VSDs are featured by a number of positively charged amino acids (arginine or lysine) located at every third position in the S4 segment. Upon membrane depolarization, movements of these charged residues in the S4 segment are coupled to the opening of the pore domain and the subsequent influx of sodium ions across cell membrane. The pore domain is structurally organized with a four-fold pseudo-symmetry. The pore (P) loops, which are supported by the P1 helix (corresponding to the P helix in potassium channel) and P2 helix between S5 and S6 segments in each repeat, constitute the selectivity filter (SF) (Corry and Thomas, 2012). Four amino acid residues (aspartate, glutamate, lysine, and alanine, DEKA, in repeats I, II, III, and IV, respectively) in the P loops are crucial for sodium selectivity. Mutating these residues to glutamates confers calcium selectivity, suggesting that the side chains of these amino acids are likely to interact directly with the sodium ions to determine ion selectivity (Heinemann et al., 1992; Sun et al., 1997).

Nav channels inactivate rapidly. A cluster of hydrophobic amino acids (isoleucine, phenylalanine, methionine, and threonine), namely the IFMT motif, located in the cytosolic regions of domain III and domain IV, are required for rapid inactivation. This is demonstrated by the fact that rapid inactivation could be achieved by titrating small peptides containing the IFMT motif (Vassilev et al., 1988; West et al., 1992).

Sodium channelopathies are a group of diseases caused by defective Nav channels, either, in most cases, of congenital nature or acquired nature (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) (George, 2005; Catterall, 2012a; Kim, 2014). For example, Nav1.1 is primarily expressed in the soma of neuronal cells in the CNS, and mutations of Nav1.1 cause GEFS+2 (generalized epilepsy with febrile seizures plus 2) (Catterall et al., 2010). Moreover, mutations of Nav1.1 are also the main causes of EIEE6 (epileptic encephalopathy, early infantile, 6) and ICEGTC (intractable childhood epilepsy with generalized tonic-clonic seizures) (Escayg and Goldin, 2010). Nav1.5 is the major sodium channel expressed in heart. Nav1.5 mutations may lead to various cardiac diseases such as LQT3 (long QT syndrome 3), BRGDA1 (Brugada syndrome 1), and SSS1 (sick sinus syndrome 1) (Olson et al., 2005; Song and Shou, 2012; Veerman et al., 2015). Nav1.7 is preferentially expressed in the sympathetic neurons, olfactory epithelium, and dorsal root ganglion sensory neurons, and plays a cardinal role in pain transmission (Djouhri et al., 2003; Dib-Hajj et al., 2013). Gain-of-function mutations of Nav1.7 are implicated in two distinct paroxysmal pain syndromes—IEM (primary erythermalgia) and PEPD (paroxysmal extreme pain disorder), while loss-of-function mutations of Nav1.7 inflict people with CIP (indifference to pain, congenital, autosomal recessive) (Lampert et al., 2010; Dib-Hajj et al., 2013). In all, Nav channel mutations play a central role in the pathophysiology of sodium channelopathies. Pharmacologic modulation of Nav channels may thereby represent a viable therapeutic approach for the treatment of many neurological disorders such as epilepsy, arrhythmia, and pain.
Table 1

Structural mapping of disease-related mutations identified in human Nav1.7

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.7

Q10R

IEM

N-terminus

Q10

hNav1.7

I62V

FEB

N-terminus

I62

hNav1.7

I136V

IEM

DI S1

I136

hNav1.7

P149Q

FEB

DI S1-S2

P149

hNav1.7

R185H

PEPD

DI S3

R185

hNav1.7

R185H

SFN

DI S3

R185

hNav1.7

S211P

IEM

DI S3-S4

S211

hNav1.7

F216S

IEM

DI S4

F216

hNav1.7

I228M

DS

DI S4

I228

hNav1.7

I228M

SFN

DI S4

I228

hNav1.7

I234T

IEM

DI S5

I234

hNav1.7

S241T

IEM

DI S5

S241

hNav1.7

L245V

IEM

DI S5

L245

hNav1.7

N395K

IEM

DI S6

N395

hNav1.7

V400M

IEM

DI S6

V400

hNav1.7

E406K

IEM

DI S6

E406

hNav1.7

S490N

FEB

DI - DII

S490

hNav1.7

E519K

DS

DI - DII

E519

hNav1.7

P610T

IEM

DI - DII

P610

hNav1.7

G616R

IEM

DI - DII

G616

hNav1.7

D623N

SFN

DI - DII

D623

hNav1.7

N641Y

FEB

DI - DII

N641

hNav1.7

K666R

FEB

DI - DII

K666

hNav1.7

K666R

DS

DI - DII

K666

hNav1.7

I695M

DS

DI - DII

I695

hNav1.7

C710Y

DS

DI - DII

C710

hNav1.7

I731K

SFN

DI - DII

I731

hNav1.7

I750V

SFN

DII S1

I750

hNav1.7

I750V

DS

DII S1

I750

hNav1.7

I750V

FEB

DII S1

I750

hNav1.7

L834R

IEM

DII S4

L834

hNav1.7

I859T

IEM

DII S5

I859

hNav1.7

G867D

IEM

DII S5

G867

hNav1.7

L869F

IEM

DII S5

L869

hNav1.7

L869H

IEM

DII S5

L869

hNav1.7

A874P

IEM

DII S5

A874

hNav1.7

V883G

IEM

DII S5

V883

hNav1.7

Q886E

IEM

DII S5

Q886

hNav1.7

R907Q

CIP

DII S5-S6

R907

hNav1.7

M943L

SFN

DII S5-S6

M943

hNav1.7

V1002L

SFN

DII - DIII

V1002

hNav1.7

R1007C

PEPD

DII - DIII

R1007

hNav1.7

L1134F

DS

DII - DIII

L1134

hNav1.7

E1171Q

DS

DII - DIII

E1171

hNav1.7

A1247E

CIP

DIII S2

A1247

hNav1.7

L1278V

DS

DIII S3-S4

L1278

hNav1.7

V1309D

PEPD

DIII S4-S5

V1309

hNav1.7

V1309F

PEPD

DIII S4-S5

V1309

hNav1.7

V1310F

PEPD

DIII S4-S5

V1310

hNav1.7

P1319L

IEM

DIII S4-S5

P1319

hNav1.7

F1460V

IEM

DIII S6

F1460

hNav1.7

I1472T

PEPD

DIII - DIV

I1472

hNav1.7

F1473V

PEPD

DIII - DIV

F1473

hNav1.7

T1475I

PEPD

DIII - DIV

T1475

hNav1.7

M1543I

SFN

DIV S2

M1543

hNav1.7

G1618R

PEPD

DIV S4

G1618

hNav1.7

L1623P

PEPD

DIV S4

L1623

hNav1.7

M1638K

PEPD

DIV S5

M1638

hNav1.7

A1643E

PEPD

DIV S5

A1643

hNav1.7

A1643E

IEM

DIV S5

A1643

hNav1.7

A1643G

IEM

DIV S5

A1643

hNav1.7

A1643T

IEM

DIV S5

A1643

hNav1.7

W1786R

CIP

C-terminus

W1786

IEM: Primary erythermalgia; PEPD: Paroxysmal extreme pain disorder; CIP: Indifference to pain, congenital, autosomal recessive; DS: Dravet syndrome; SFN: Small fiber neuropathy; FEB: Febrile seizures

Table 2

Structural mapping of disease-related mutations identified in human Nav1.1

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.1

R27T

GEFS+2

N-terminus

Q25

hNav1.1

S74P

GEFS+2

N-terminus

S72

hNav1.1

D188V

GEFS+2

DI S3

D186

hNav1.1

F218L

GEFS+2

DI S4

F216

hNav1.1

T254I

GEFS+2

DI S5

T252

hNav1.1

S291G

GEFS+2

DI S5-S6

S279

hNav1.1

R377Q

GEFS+2

DI S5-S6

R356

hNav1.1

Y388H

GEFS+2

DI S5-S6

Y367

hNav1.1

Y790C

GEFS+2

DII S1-S2

H766

hNav1.1

R859C

GEFS+2

DII S4

R835

hNav1.1

R859H

GEFS+2

DII S4

R835

hNav1.1

T875M

GEFS+2

DII S4-S5

T851

hNav1.1

I899T

GEFS+2

DII S5

I875

hNav1.1

N935H

GEFS+2

DII S5-S6

N911

hNav1.1

R946H

GEFS+2

DII S5-S6

R922

hNav1.1

M960T

GEFS+2

DII S5-S6

M936

hNav1.1

M973V

GEFS+2

DII S6

M949

hNav1.1

M976I

GEFS+2

DII S6

M952

hNav1.1

I978M

GEFS+2

DII S6

I954

hNav1.1

W1204R

GEFS+2

DII - DIII

W1178

hNav1.1

W1204S

GEFS+2

DII - DIII

W1178

hNav1.1

L1230F

GEFS+2

DIII S1

L1204

hNav1.1

K1249N

GEFS+2

DIII S2

K1223

hNav1.1

T1250M

GEFS+2

DIII S2

I1224

hNav1.1

K1270T

GEFS+2

DIII S2

K1244

hNav1.1

L1309F

GEFS+2

DIII S3-S4

L1283

hNav1.1

V1353L

GEFS+2

DIII S5

V1327

hNav1.1

V1366I

GEFS+2

DIII S5

V1340

hNav1.1

N1414D

GEFS+2

DIII S5-S6

N1388

hNav1.1

V1428A

GEFS+2

DIII S5-S6

V1402

hNav1.1

R1596H

GEFS+2

DIV S2-S3

R1570

hNav1.1

R1648H

GEFS+2

DIV S4

R1622

hNav1.1

I1656M

GEFS+2

DIV S5

I1630

hNav1.1

R1657C

GEFS+2

DIV S5

R1631

hNav1.1

A1685V

GEFS+2

DIV S5

A1659

hNav1.1

F1687S

GEFS+2

DIV S5

F1661

hNav1.1

P1739L

GEFS+2

DIV S5-S6

P1713

hNav1.1

D1742G

GEFS+2

DIV S5-S6

D1716

hNav1.1

F1765L

GEFS+2

DIV S6

Y1739

hNav1.1

E1795K

GEFS+2

C-terminus

E1769

hNav1.1

M1852T

GEFS+2

C-terminus

M1826

hNav1.1

V1857L

GEFS+2

C-terminus

V1831

hNav1.1

D1866Y

GEFS+2

C-terminus

D1840

hNav1.1

I1867T

GEFS+2

C-terminus

I1841

hNav1.1

G58V

EIEE6

N-terminus

G56

hNav1.1

L61F

EIEE6

N-terminus

L59

hNav1.1

F63L

EIEE6

N-terminus

F61

hNav1.1

I68T

EIEE6

N-terminus

I66

hNav1.1

E78D

EIEE6

N-terminus

E76

hNav1.1

D79H

EIEE6

N-terminus

D77

hNav1.1

D79N

EIEE6

N-terminus

D77

hNav1.1

Y84C

EIEE6

N-terminus

Y82

hNav1.1

F90S

EIEE6

N-terminus

F88

hNav1.1

I91T

EIEE6

N-terminus

I89

hNav1.1

A98P

EIEE6

N-terminus

T96

hNav1.1

R101Q

EIEE6

N-terminus

R99

hNav1.1

R101W

EIEE6

N-terminus

R99

hNav1.1

S103G

EIEE6

N-terminus

N101

hNav1.1

T105I

EIEE6

N-terminus

T103

hNav1.1

L108R

EIEE6

N-terminus

L106

hNav1.1

T112I

EIEE6

N-terminus

S110

hNav1.1

R118S

EIEE6

N-terminus

R116

hNav1.1

I124N

EIEE6

N-terminus

I122

hNav1.1

H127D

EIEE6

N-terminus

H125

hNav1.1

T162P

EIEE6

DI S2

T160

hNav1.1

I171K

EIEE6

DI S2

V169

hNav1.1

I171R

EIEE6

DI S2

V169

hNav1.1

A175T

EIEE6

DI S2-23

A173

hNav1.1

A175V

EIEE6

DI S2-S3

A173

hNav1.1

G177E

EIEE6

DI S2-S3

G175

hNav1.1

C179R

EIEE6

DI S2-S3

C177

hNav1.1

W190R

EIEE6

DI S3

W188

hNav1.1

N191K

EIEE6

DI S3

N189

hNav1.1

N191Y

EIEE6

DI S3

N189

hNav1.1

D194G

EIEE6

DI S3

D192

hNav1.1

D194N

EIEE6

DI S3

D192

hNav1.1

T199R

EIEE6

DI S3

V197

hNav1.1

T217K

EIEE6

DI S3-S4

T215

hNav1.1

A223E

EIEE6

DI S4

A221

hNav1.1

T226M

EIEE6

DI S4

T224

hNav1.1

T226R

EIEE6

DI S4

T224

hNav1.1

I227S

EIEE6

DI S4

I225

hNav1.1

I227T

EIEE6

DI S4

I225

hNav1.1

G232S

EIEE6

DI S4-S5

G230

hNav1.1

L233R

EIEE6

DI S5

L231

hNav1.1

A239T

EIEE6

DI S5

A237

hNav1.1

A239V

EIEE6

DI S5

A237

hNav1.1

S243Y

EIEE6

DI S5

S241

hNav1.1

I252N

EIEE6

DI S5

I250

hNav1.1

S259R

EIEE6

DI S5

S257

hNav1.1

G265W

EIEE6

DI S5

G263

hNav1.1

C277R

EIEE6

DI S5-S6

C275

hNav1.1

W280C

EIEE6

DI S5-S6

N278

hNav1.1

W280R

EIEE6

DI S5-S6

N278

hNav1.1

P281A

EIEE6

DI S5-S6

S279

hNav1.1

P281L

EIEE6

DI S5-S6

S279

hNav1.1

P281S

EIEE6

DI S5-S6

S279

hNav1.1

E289V

EIEE6

DI S5-S6

E287

hNav1.1

T297I

EIEE6

DI S5-S6

hNav1.1

R322I

EIEE6

DI S5-S6

R301

hNav1.1

S340F

EIEE6

DI S5-S6

T319

hNav1.1

A342V

EIEE6

DI S5-S6

S321

hNav1.1

G343D

EIEE6

DI S5-S6

G322

hNav1.1

C345R

EIEE6

DI S5-S6

C324

hNav1.1

C351W

EIEE6

DI S5-S6

C330

hNav1.1

G355D

EIEE6

DI S5-S6

G334

hNav1.1

R356G

EIEE6

DI S5-S6

R335

hNav1.1

N357I

EIEE6

DI S5-S6

N336

hNav1.1

P358T

EIEE6

DI S5-S6

P357

hNav1.1

N359S

EIEE6

DI S5-S6

D338

hNav1.1

T363P

EIEE6

DI S5-S6

T342

hNav1.1

T363R

EIEE6

DI S5-S6

T342

hNav1.1

D366E

EIEE6

DI S5-S6

D345

hNav1.1

L378Q

EIEE6

DI S5-S6

L357

hNav1.1

M379R

EIEE6

DI S5-S6

M358

hNav1.1

F383L

EIEE6

DI S5-S6

Y362

hNav1.1

W384R

EIEE6

DI S5-S6

M363

hNav1.1

R393C

EIEE6

DI S5-S6

R372

hNav1.1

R393H

EIEE6

DI S5-S6

R372

hNav1.1

R393S

EIEE6

DI S5-S6

R372

hNav1.1

M400V

EIEE6

DI S5-S6

M379

hNav1.1

F403L

EIEE6

DI S6

F383

hNav1.1

F403V

EIEE6

DI S6

F382

hNav1.1

V406F

EIEE6

DI S6

V385

hNav1.1

L409W

EIEE6

DI S6

L388

hNav1.1

Y413N

EIEE6

DI S6

Y392

hNav1.1

Y426C

EIEE6

DI S6

Y405

hNav1.1

Y426N

EIEE6

DI S6

Y405

hNav1.1

S525F

EIEE6

DI - DII

S505

hNav1.1

S626G

EIEE6

DI - DII

S606

hNav1.1

D674G

EIEE6

DI - DII

D651

hNav1.1

N762D

EIEE6

DI - DII

Y738

hNav1.1

L783P

EIEE6

DII S1

L759

hNav1.1

M785T

EIEE6

DII S1-S2

M761

hNav1.1

T812I

EIEE6

DII S2

A788

hNav1.1

T812R

EIEE6

DII S2

A788

hNav1.1

L842R

EIEE6

DII S3

L818

hNav1.1

S843R

EIEE6

DII S3

S819

hNav1.1

E846K

EIEE6

DII S3

E822

hNav1.1

R859C

EIEE6

DII S4

R835

hNav1.1

R862Q

EIEE6

DII S4

R838

hNav1.1

R865G

EIEE6

DII S4

R841

hNav1.1

T875K

EIEE6

DII S4-S5

T851

hNav1.1

T875M

EIEE6

DII S4-S5

T851

hNav1.1

L876I

EIEE6

DII S5

L852

hNav1.1

L890P

EIEE6

DII S5

L866

hNav1.1

V896F

EIEE6

DII S5

V872

hNav1.1

V896L

EIEE6

DII S5

V872

hNav1.1

F902C

EIEE6

DII S5

F878

hNav1.1

C927F

EIEE6

DII S5-S6

C903

hNav1.1

R931C

EIEE6

DII S5-S6

R907

hNav1.1

W932C

EIEE6

DII S5-S6

W908

hNav1.1

H933P

EIEE6

DII S5-S6

H909

hNav1.1

M934I

EIEE6

DII S5-S6

M910

hNav1.1

H939P

EIEE6

DII S5-S6

H915

hNav1.1

H939Q

EIEE6

DII S5-S6

H915

hNav1.1

H939Y

EIEE6

DII S5-S6

H915

hNav1.1

S940F

EIEE6

DII S5-S6

S916

hNav1.1

L942P

EIEE6

DII S5-S6

L918

hNav1.1

I943N

EIEE6

DII S5-S6

I919

hNav1.1

V944A

EIEE6

DII S5-S6

V920

hNav1.1

V944E

EIEE6

DII S5-S6

V920

hNav1.1

F945L

EIEE6

DII S5-S6

F921

hNav1.1

R946C

EIEE6

DII S5-S6

R922

hNav1.1

R946H

EIEE6

DII S5-S6

R922

hNav1.1

R946S

EIEE6

DII S5-S6

R922

hNav1.1

C949S

EIEE6

DII S5-S6

C925

hNav1.1

C949Y

EIEE6

DII S5-S6

C925

hNav1.1

G950E

EIEE6

DII S5-S6

G926

hNav1.1

G950R

EIEE6

DII S5-S6

G926

hNav1.1

W952G

EIEE6

DII S5-S6

W928

hNav1.1

E954K

EIEE6

DII S5-S6

E930

hNav1.1

M956K

EIEE6

DII S5-S6

M932

hNav1.1

W957L

EIEE6

DII S5-S6

W933

hNav1.1

C959R

EIEE6

DII S5-S6

C935

hNav1.1

M960V

EIEE6

DII S5-S6

M936

hNav1.1

M973K

EIEE6

DII S6

M949

hNav1.1

M976I

EIEE6

DII S6

M952

hNav1.1

G979V

EIEE6

DII S6

G955

hNav1.1

N985I

EIEE6

DII S6

N961

hNav1.1

L986F

EIEE6

DII S6

L962

hNav1.1

L986P

EIEE6

DII S6

L962

hNav1.1

F987L

EIEE6

DII S6

F963

hNav1.1

S993R

EIEE6

DII - DIII

S969

hNav1.1

D998G

EIEE6

DII - DIII

D974

hNav1.1

E1068K

EIEE6

DII - DIII

E1045

hNav1.1

L1207P

EIEE6

DII - DIII

I1181

hNav1.1

R1208K

EIEE6

DII - DIII

R1182

hNav1.1

T1210K

EIEE6

DII - DIII

T1184

hNav1.1

E1221K

EIEE6

DIII S1

E1195

hNav1.1

L1230F

EIEE6

DIII S1

L1204

hNav1.1

S1231R

EIEE6

DIII S1

S1205

hNav1.1

S1231T

EIEE6

DIII S1

S1205

hNav1.1

G1233R

EIEE6

DIII S1

G1207

hNav1.1

E1238D

EIEE6

DIII S1-S2

E1212

hNav1.1

D1239G

EIEE6

DIII S1-S2

D1213

hNav1.1

D1239Y

EIEE6

DIII S1-S2

D1213

hNav1.1

R1245Q

EIEE6

DIII S1-S2

K1219

hNav1.1

A1255D

EIEE6

DIII S2

A1229

hNav1.1

T1260P

EIEE6

DIII S2

T1234

hNav1.1

F1263L

EIEE6

DIII S2

F1237

hNav1.1

L1265P

EIEE6

DIII S2

L1239

hNav1.1

E1266A

EIEE6

DIII S2

E1240

hNav1.1

G1275V

EIEE6

DIII S2-S3

G1249

hNav1.1

W1284S

EIEE6

DIII S3

W1258

hNav1.1

L1287P

EIEE6

DIII S3

L1261

hNav1.1

D1288N

EIEE6

DIII S3

D1262

hNav1.1

R1316G

EIEE6

DIII S4

R1290

hNav1.1

R1316S

EIEE6

DIII S4

R1290

hNav1.1

A1320V

EIEE6

DIII S4

A1294

hNav1.1

A1326P

EIEE6

DIII S4

A1300

hNav1.1

S1328P

EIEE6

DIII S4-S5

S1302

hNav1.1

V1335M

EIEE6

DIII S4-S5

V1309

hNav1.1

A1339V

EIEE6

DIII S4-S5

A1313

hNav1.1

I1344M

EIEE6

DIII S4-S5

I1318

hNav1.1

V1350G

EIEE6

DIII S5

V1324

hNav1.1

L1355P

EIEE6

DIII S5

L1329

hNav1.1

W1358R

EIEE6

DIII S5

W1332

hNav1.1

W1358S

EIEE6

DIII S5

W1332

hNav1.1

N1367K

EIEE6

DIII S5

N1341

hNav1.1

A1370P

EIEE6

DIII S5-S6

A1344

hNav1.1

N1378H

EIEE6

DIII S5-S6

N1352

hNav1.1

N1378T

EIEE6

DIII S5-S6

N1352

hNav1.1

F1385V

EIEE6

DIII S5-S6

F1359

hNav1.1

V1390M

EIEE6

DIII S5-S6

V1364

hNav1.1

N1391S

EIEE6

DIII S5-S6

P1365

hNav1.1

H1393P

EIEE6

DIII S5-S6

R1367

hNav1.1

T1394I

EIEE6

DIII S5-S6

S1368

hNav1.1

C1396G

EIEE6

DIII S5-S6

C1370

hNav1.1

C1396Y

EIEE6

DIII S5-S6

C1370

hNav1.1

N1414Y

EIEE6

DIII S5-S6

N1388

hNav1.1

D1416G

EIEE6

DIII S5-S6

D1390

hNav1.1

N1417S

EIEE6

DIII S5-S6

N1391

hNav1.1

V1418G

EIEE6

DIII S5-S6

V1392

hNav1.1

Y1422C

EIEE6

DIII S5-S6

Y1396

hNav1.1

L1423F

EIEE6

DIII S5-S6

L1397

hNav1.1

L1426R

EIEE6

DIII S5-S6

L1400

hNav1.1

Q1427P

EIEE6

DIII S5-S6

Q1401

hNav1.1

F1431I

EIEE6

DIII S5-S6

F1405

hNav1.1

G1433E

EIEE6

DIII S5-S6

G1407

hNav1.1

G1433R

EIEE6

DIII S5-S6

G1407

hNav1.1

G1433V

EIEE6

DIII S5-S6

G1407

hNav1.1

W1434R

EIEE6

DIII S5-S6

W1408

hNav1.1

I1437M

EIEE6

DIII S5-S6

I1411

hNav1.1

A1441P

EIEE6

DIII S5-S6

A1415

hNav1.1

Q1450K

EIEE6

DIII S5-S6

Q1424

hNav1.1

Q1450R

EIEE6

DIII S5-S6

Q1424

hNav1.1

P1451L

EIEE6

DIII S5-S6

P1425

hNav1.1

P1451S

EIEE6

DIII S5-S6

P1425

hNav1.1

Y1453C

EIEE6

DIII S5-S6

Y1427

hNav1.1

E1454K

EIEE6

DIII S5-S6

E1428

hNav1.1

L1461I

EIEE6

DIII S6

I1435

hNav1.1

Y1462C

EIEE6

DIII S6

Y1436

hNav1.1

Y1462H

EIEE6

DIII S6

Y1436

hNav1.1

F1463S

EIEE6

DIII S6

F1437

hNav1.1

G1470W

EIEE6

DIII S6

G1444

hNav1.1

F1472S

EIEE6

DIII S6

F1446

hNav1.1

L1475S

EIEE6

DIII S6

L1449

hNav1.1

N1476K

EIEE6

DIII S6

N1450

hNav1.1

D1484G

EIEE6

DIII S6

D1458

hNav1.1

N1485Y

EIEE6

DIII S6

N1459

hNav1.1

E1503K

EIEE6

DIII - DIV

E1477

hNav1.1

L1514S

EIEE6

DIII - DIV

L1488

hNav1.1

V1538I

EIEE6

DIII - DIV

V1512

hNav1.1

D1544A

EIEE6

DIV S1

D1518

hNav1.1

D1544G

EIEE6

DIV S1

D1518

hNav1.1

I1545V

EIEE6

DIV S1

I1519

hNav1.1

M1555R

EIEE6

DIV S1

M1529

hNav1.1

E1561K

EIEE6

DIV S1-S2

E1535

hNav1.1

V1579E

EIEE6

DIV S2

V1553

hNav1.1

G1586E

EIEE6

DIV S2

G1560

hNav1.1

C1588R

EIEE6

DIV S2

C1562

hNav1.1

L1592H

EIEE6

DIV S2

L1566

hNav1.1

L1592P

EIEE6

DIV S2

L1566

hNav1.1

R1596C

EIEE6

DIV S2-S3

R1570

hNav1.1

R1596L

EIEE6

DIV S2-S3

R1570

hNav1.1

N1605S

EIEE6

DIV S3

N1579

hNav1.1

D1608G

EIEE6

DIV S3

D1582

hNav1.1

D1608Y

EIEE6

DIV S3

D1582

hNav1.1

V1612I

EIEE6

DIV S3

V1586

hNav1.1

V1630L

EIEE6

DIV S3-S4

V1604

hNav1.1

V1630M

EIEE6

DIV S3-S4

V1604

hNav1.1

V1637E

EIEE6

DIV S4

V1611

hNav1.1

I1638N

EIEE6

DIV S4

I1612

hNav1.1

I1638T

EIEE6

DIV S4

I1612

hNav1.1

R1639G

EIEE6

DIV S4

R1613

hNav1.1

R1642S

EIEE6

DIV S4

R1616

hNav1.1

R1645Q

EIEE6

DIV S4

R1619

hNav1.1

R1648C

EIEE6

DIV S4

R1622

hNav1.1

R1648H

EIEE6

DIV S4

R1622

hNav1.1

A1653E

EIEE6

DIV S4-S5

A1627

hNav1.1

T1658M

EIEE6

DIV S5

T1632

hNav1.1

T1658R

EIEE6

DIV S5

T1632

hNav1.1

L1660P

EIEE6

DIV S5

L1634

hNav1.1

F1661S

EIEE6

DIV S5

F1635

hNav1.1

A1662V

EIEE6

DIV S5

A1636

hNav1.1

M1664K

EIEE6

DIV S5

M1638

hNav1.1

L1667P

EIEE6

DIV S5

L1641

hNav1.1

P1668A

EIEE6

DIV S5

P1642

hNav1.1

P1668L

EIEE6

DIV S5

P1642

hNav1.1

N1672I

EIEE6

DIV S5

N1646

hNav1.1

I1673T

EIEE6

DIV S5

I1647

hNav1.1

G1674R

EIEE6

DIV S5

G1648

hNav1.1

L1675R

EIEE6

DIV S5

L1649

hNav1.1

L1677F

EIEE6

DIV S5

L1651

hNav1.1

I1683T

EIEE6

DIV S5

I1657

hNav1.1

Y1684D

EIEE6

DIV S5

Y1658

hNav1.1

A1685D

EIEE6

DIV S5

A1659

hNav1.1

G1688W

EIEE6

DIV S5

G1662

hNav1.1

F1692S

EIEE6

DIV S5

F1666

hNav1.1

Y1694C

EIEE6

DIV S5-S6

Y1668

hNav1.1

F1707V

EIEE6

DIV S5-S6

F1681

hNav1.1

S1713N

EIEE6

DIV S5-S6

S1687

hNav1.1

M1714K

EIEE6

DIV S5-S6

M1688

hNav1.1

M1714R

EIEE6

DIV S5-S6

M1688

hNav1.1

C1716R

EIEE6

DIV S5-S6

C1690

hNav1.1

T1721R

EIEE6

DIV S5-S6

T1695

hNav1.1

G1725C

EIEE6

DIV S5-S6

G1699

hNav1.1

W1726R

EIEE6

DIV S5-S6

W1700

hNav1.1

D1727G

EIEE6

DIV S5-S6

D1701

hNav1.1

C1741R

EIEE6

DIV S5-S6

C1715

hNav1.1

G1749E

EIEE6

DIV S5-S6

G1723

hNav1.1

C1756G

EIEE6

DIV S5-S6

C1730

hNav1.1

G1762E

EIEE6

DIV S6

G1736

hNav1.1

I1763N

EIEE6

DIV S6

I1737

hNav1.1

I1770F

EIEE6

DIV S6

I1744

hNav1.1

I1770N

EIEE6

DIV S6

I1744

hNav1.1

I1770T

EIEE6

DIV S6

I1744

hNav1.1

I1771F

EIEE6

DIV S6

I1745

hNav1.1

I1771N

EIEE6

DIV S6

I1745

hNav1.1

S1773F

EIEE6

DIV S6

S1747

hNav1.1

M1780T

EIEE6

DIV S6

M1754

hNav1.1

Y1781C

EIEE6

DIV S6

Y1755

hNav1.1

Y1781H

EIEE6

DIV S6

Y1755

hNav1.1

I1782M

EIEE6

DIV S6

I1756

hNav1.1

I1782S

EIEE6

DIV S6

I1756

hNav1.1

A1783T

EIEE6

DIV S6

A1757

hNav1.1

A1783V

EIEE6

DIV S6

A1757

hNav1.1

E1787K

EIEE6

DIV S6

E1761

hNav1.1

N1788K

EIEE6

DIV S6

N1862

hNav1.1

A1792T

EIEE6

C-terminus

A1766

hNav1.1

F1808I

EIEE6

C-terminus

F1782

hNav1.1

W1812G

EIEE6

C-terminus

W1786

hNav1.1

W1812S

EIEE6

C-terminus

W1786

hNav1.1

F1831S

EIEE6

C-terminus

F1805

hNav1.1

A1832P

EIEE6

C-terminus

A1806

hNav1.1

L1835F

EIEE6

C-terminus

L1809

hNav1.1

M1852K

EIEE6

C-terminus

M1826

hNav1.1

P1855L

EIEE6

C-terminus

P1829

hNav1.1

G1880E

EIEE6

C-terminus

G1854

hNav1.1

E1881D

EIEE6

C-terminus

E1855

hNav1.1

T1909I

EIEE6

C-terminus

T1883

hNav1.1

I1922T

EIEE6

C-terminus

I1896

hNav1.1

F90S

ICEGTC

N-terminus

F88

hNav1.1

R101Q

ICEGTC

N-terminus

R99

hNav1.1

F178S

ICEGTC

DI S2-S3

F176

hNav1.1

I252M

ICEGTC

DI S5

I250

hNav1.1

H290R

ICEGTC

DI S5-S6

S288

hNav1.1

R393H

ICEGTC

DI S5-S6

R372

hNav1.1

T808S

ICEGTC

DII S2

T784

hNav1.1

V896I

ICEGTC

DII S5

V872

hNav1.1

V944A

ICEGTC

DII S5-S6

R920

hNav1.1

G979R

ICEGTC

DII S6

G955

hNav1.1

V983A

ICEGTC

DII S6

V959

hNav1.1

N1011I

ICEGTC

DII - DIII

N987

hNav1.1

R1213Q

ICEGTC

DII - DIII

K1187

hNav1.1

Y1254C

ICEGTC

DIII S2

Y1228

hNav1.1

R1325T

ICEGTC

DIII S4

R1299

hNav1.1

S1328P

ICEGTC

DIII S4-S5

S1302

hNav1.1

F1357L

ICEGTC

DIII S5

F1331

hNav1.1

V1366I

ICEGTC

DIII S5

V1340

hNav1.1

C1376R

ICEGTC

DIII S5-S6

C1350

hNav1.1

A1429D

ICEGTC

DIII S5-S6

A1403

hNav1.1

Y1462H

ICEGTC

DIII S6

Y1436

hNav1.1

M1511K

ICEGTC

DIII - DIV

M1485

hNav1.1

V1611F

ICEGTC

DIV S3

V1585

hNav1.1

M1619V

ICEGTC

DIV S3

M1593

hNav1.1

P1632S

ICEGTC

DIV S3-S4

P1606

hNav1.1

Y1684S

ICEGTC

DIV S5

Y1658

hNav1.1

T1709I

ICEGTC

DIV S5-S6

T1683

hNav1.1

A1724P

ICEGTC

DIV S5-S6

A1698

hNav1.1

Y1781C

ICEGTC

DIV S6

Y1755

hNav1.1

F1808L

ICEGTC

C-terminus

F1782

hNav1.1

R1861W

ICEGTC

C-terminus

R1835

hNav1.1

T1174S

FHM3

DII - DIII

S1148

hNav1.1

Q1489H

FHM3

DIII S6

Q1463

hNav1.1

Q1489K

FHM3

DIII S6

Q1463

hNav1.1

F1499L

FHM3

DIII - DIV

F1473

hNav1.1

L1649Q

FHM3

DIV S4

L1623

hNav1.1

M145T

FEB3A

DI S1

M143

hNav1.1

E1308D

FEB3A

DIII S3-S4

D1282

GEFS+2: Generalized epilepsy with febrile seizures plus 2; EIEE6: Epileptic encephalopathy, early infantile, 6; ICEGTC: Intractable childhood epilepsy with generalized tonic-clonic seizures; FHM3: Migraine, familial hemiplegic, 3; FEB3A: Febrile seizures, familial, 3A

Table 3

Structural mapping of disease-related mutations identified in human Nav1.2

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.2

E169G

EIEE11

DI S2

E166

hNav1.2

R188W

BFIS3

DI S3

R185

hNav1.2

V208E

BFIS3

DI S3-S4

V205

hNav1.2

N212D

EIEE11

DI S3-S4

N209

hNav1.2

V213D

EIEE11

DI S3-S4

V210

hNav1.2

R223Q

BFIS3

DI S4

R220

hNav1.2

T236S

EIEE11

DI S5

T233

hNav1.2

M252V

BFIS3

DI S5

M249

hNav1.2

V261M

BFIS3

DI S5

V258

hNav1.2

A263T

EIEE11

DI S5

A260

hNav1.2

A263V

EIEE11

DI S5

A260

hNav1.2

D322N

DS

DI - DII

D298

hNav1.2

F328V

DS

DI - DII

Y305

hNav1.2

E430Q

BFIS3

DI - DII

E407

hNav1.2

D649N

DS

DI - DII

D623

hNav1.2

R853Q

EIEE11

DII S4

R838

hNav1.2

N876T

EIEE11

DII S5

N861

hNav1.2

V892I

BFIS3

DII S5

V877

hNav1.2

E999K

EIEE11

DII - DIII

D984

hNav1.2

N1001K

BFIS3

DII - DIII

N986

hNav1.2

L1003I

BFIS3

DII - DIII

L988

hNav1.2

E1211K

EIEE11

DIII S1

E1195

hNav1.2

R1312T

EIEE11

DIII S4

R1296

hNav1.2

R1312T

DS

DIII S4

R1296

hNav1.2

R1319Q

BFIS3

DIII S4-S5

R1303

hNav1.2

M1323V

EIEE11

DIII S4-S5

M1307

hNav1.2

V1326L

EIEE11

DIII S4-S5

V1310

hNav1.2

V1326D

EIEE11

DIII S4-S5

V1310

hNav1.2

L1330F

BFIS3

DIII S4-S5

L1314

hNav1.2

S1336Y

EIEE11

DIII S4-S5

S1320

hNav1.2

M1338T

EIEE11

DIII S5

M1322

hNav1.2

L1342P

BFIS3

DIII S5

L1326

hNav1.2

I1473M

EIEE11

DIII S6

I1457

hNav1.2

L1563V

BFIS3

DIV S2

L1547

hNav1.2

Y1589C

BFIS3

DIV S2-S3

Y1573

hNav1.2

I1596S

BFIS3

DIV S3

I1580

hNav1.2

T1623N

EIEE11

DIV S3-S4

T1607

hNav1.2

R1629L

EIEE11

DIV S4

R1613

hNav1.2

L1660Y

EIEE11

DIV S5

L1644

hNav1.2

R1918H

BFIS3

C-terminus

R1902

BFIS3: Seizures, benign familial infantile 3; EIEE11: Epileptic encephalopathy, early infantile, 11; DS: Dravet syndrome

Table 4

Structural mapping of disease-related mutations identified in human Nav1.3

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.3

K354Q

CPE

DI - DII

K332

hNav1.3

R357Q

CPE

DI - DII

R335

hNav1.3

D815N

CPE

DII S2-S3

D799

hNav1.3

E1160K

CPE

DII - DIII

M1146

hNav1.3

M1372V

CPE

DIII S5-S6

R1358

hNav1.3

G1862C

CPE

C-terminus

G1851

CPE: Cryptogenic partial epilepsy

Table 5

Structural mapping of disease-related mutations identified in human Nav1.4

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.4

Q270K

PMC

DI S5

Q265

hNav1.4

I693T

PMC

DII S5

I858

hNav1.4

T704M

PMC

DII S5

T870

hNav1.4

S804F

PMC

DII - DIII

S970

hNav1.4

A1152D

PMC

DIII S4-S5

A1313

hNav1.4

A1156T

PMC

DIII S4-S5

A1317

hNav1.4

V1293I

PMC

DIII S6

V1455

hNav1.4

G1306A

PMC

DIII S6

G1468

hNav1.4

G1306E

PMC

DIII S6

G1468

hNav1.4

G1306V

PMC

DIII S6

G1468

hNav1.4

T1313M

PMC

DIII - DIV

T1475

hNav1.4

L1433R

PMC

DIV S3

L1595

hNav1.4

L1436P

PMC

DIV S3

L1598

hNav1.4

R1448C

PMC

DIV S4

R1610

hNav1.4

R1448H

PMC

DIV S4

R1610

hNav1.4

R1448L

PMC

DIV S4

R1610

hNav1.4

G1456E

PMC

DIV S4

G1618

hNav1.4

F1473S

PMC

DIV S5

F1635

hNav1.4

V1589M

PMC

DIV S6

V1751

hNav1.4

F1705I

PMC

C-terminus

F1867

hNav1.4

R222W

HOKPP2

DI S4

E217

hNav1.4

R669H

HOKPP2

DII S4

R835

hNav1.4

R672C

HOKPP2

DII S4

R838

hNav1.4

R672G

HOKPP2

DII S4

R838

hNav1.4

R672H

HOKPP2

DII S4

R838

hNav1.4

R672S

HOKPP2

DII S4

R838

hNav1.4

R1129Q

HOKPP2

DIII S4

R1290

hNav1.4

R1132Q

HOKPP2

DIII S4

R1293

hNav1.4

R1135C

HOKPP2

DIII S4

R1296

hNav1.4

R1135H

HOKPP2

DIII S4

R1299

hNav1.4

P1158S

HOKPP2

DIII S4-S5

P1319

hNav1.4

T704M

HYPP

DII S5

T870

hNav1.4

V781I

HYPP

DII S6

V947

hNav1.4

A1156T

HYPP

DIII S4-S5

A1317

hNav1.4

L1433R

HYPP

DIV S3

L1595

hNav1.4

M1592V

HYPP

DIV S6

M1754

hNav1.4

R675G

NKPP

DII S4

R841

hNav1.4

R675Q

NKPP

DII S4

R841

hNav1.4

R675W

NKPP

DII S4

R841

hNav1.4

V781I

NKPP

DII S6

V947

hNav1.4

R1129Q

NKPP

DIII S4

R1290

hNav1.4

M1592V

NKPP

DIV S6

M1754

hNav1.4

I141V

MYOSCN4A

DI S1

I136

hNav1.4

R225W

MYOSCN4A

DI S4

R220

hNav1.4

N440K

MYOSCN4A

DI S6

N395

hNav1.4

V445M

MYOSCN4A

DI - DII

V440

hNav1.4

E452K

MYOSCN4A

DI - DII

E447

hNav1.4

I588V

MYOSCN4A

DII S1

I754

hNav1.4

F671S

MYOSCN4A

DII S4

F837

hNav1.4

A715T

MYOSCN4A

DII S5

A881

hNav1.4

S804N

MYOSCN4A

DII - DIII

S970

hNav1.4

A1156T

MYOSCN4A

DIII S4-S5

A1317

hNav1.4

P1158L

MYOSCN4A

DIII S4-S5

P1319

hNav1.4

I1160V

MYOSCN4A

DIII S4-S5

I1321

hNav1.4

N1297K

MYOSCN4A

DIII S6

I1457

hNav1.4

G1306E

MYOSCN4A

DIII S6

G1468

hNav1.4

G1306V

MYOSCN4A

DIII S6

G1468

hNav1.4

I1310N

MYOSCN4A

DIII - DIV

I1472

hNav1.4

M1476I

MYOSCN4A

DIV S5

M1638

hNav1.4

A1481D

MYOSCN4A

DIV S5

A1643

hNav1.4

Q1633E

MYOSCN4A

C-terminus

Q1795

hNav1.4

R104H

CMS16

N-terminus

R99

hNav1.4

M203K

CMS16

DI S3

F198

hNav1.4

R225W

CMS16

DI S4

R220

hNav1.4

S246L

CMS16

DI S5

S241

hNav1.4

P382T

CMS16

DI S5-S6

P337

hNav1.4

D1069N

CMS16

DIII S2

D1230

hNav1.4

R1135C

CMS16

DIII S4-S5

R1299

hNav1.4

C1209F

CMS16

DIII S5-S6

C1370

hNav1.4

V1442E

CMS16

DIV S3-S4

V1604

hNav1.4

R1454W

CMS16

DIV S4

R1616

hNav1.4

R1457H

CMS16

DIV S4

R1619

PMC: Paramyotonia congenita of von Eulenburg; HOKPP2: Periodic paralysis hypokalemic 2; HYPP: Periodic paralysis hyperkalemic; NKPP: Periodic paralysis normokalemic; MYOSCN4A: Myotonia SCN4A-related; CMS16: Myasthenic syndrome, congenital, 16

Table 6

Structural mapping of disease-related mutations identified in human Nav1.5

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.5

E161K

PFHB1A

DI S2

E156

hNav1.5

R225W

PFHB1A

DI S4

R220

hNav1.5

G298S

PFHB1A

DI S4-S5

hNav1.5

T512I

PFHB1A

DI - DII

V518

hNav1.5

G514C

PFHB1A

DI - DII

G520

hNav1.5

G752R

PFHB1A

DII S2-S3

G779

hNav1.5

R1232W

PFHB1A

DIII S1-S2

K1219

hNav1.5

D1275N

PFHB1A

DIII S3

D1262

hNav1.5

D1595N

PFHB1A

DIII D3-S4

D1582

hNav1.5

T1620K

PFHB1A

DIV S3-S4

T1607

hNav1.5

G9V

LQT3

N-terminus

G8

hNav1.5

R18Q

LQT3

N-terminus

K17

hNav1.5

R27H

LQT3

N-terminus

R26

hNav1.5

E30G

LQT3

N-terminus

E29

hNav1.5

R43Q

LQT3

N-terminus

K40

hNav1.5

E48K

LQT3

N-terminus

D43

hNav1.5

P52S

LQT3

N-terminus

P47

hNav1.5

R53Q

LQT3

N-terminus

K48

hNav1.5

R104G

LQT3

N-terminus

R99

hNav1.5

S115G

LQT3

N-terminus

S110

hNav1.5

V125L

LQT3

N-terminus

I125

hNav1.5

L212P

LQT3

DI S3-S4

L207

hNav1.5

R222Q

LQT3

DI S4

R217

hNav1.5

R225Q

LQT3

DI S4

R220

hNav1.5

R225W

LQT3

DI S4

R220

hNav1.5

V240M

LQT3

DI S5

V235

hNav1.5

Q245K

LQT3

DI S5

Q240

hNav1.5

V247L

LQT3

DI S5

L242

hNav1.5

N275K

LQT3

DI S5-S6

N270

hNav1.5

G289S

LQT3

DI S5-S6

E284

hNav1.5

R340W

LQT3

DI S5-S6

T329

hNav1.5

R367C

LQT3

DI S5-S6

R356

hNav1.5

T370M

LQT3

DI S5-S6

T359

hNav1.5

I397T

LQT3

DI S6

I386

hNav1.5

L404Q

LQT3

DI S6

L393

hNav1.5

N406K

LQT3

DI S6

N395

hNav1.5

L409V

LQT3

DI S6

L398

hNav1.5

V411M

LQT3

DI S6

V400

hNav1.5

A413E

LQT3

DI S6

A402

hNav1.5

A413T

LQT3

DI S6

A402

hNav1.5

E462A

LQT3

DI - DII

E464

hNav1.5

E462K

LQT3

DI - DII

E464

hNav1.5

F530V

LQT3

DI - DII

F555

hNav1.5

R535Q

LQT3

DI - DII

R562

hNav1.5

R569W

LQT3

DI - DII

E596

hNav1.5

S571I

LQT3

DI - DII

R598

hNav1.5

A572D

LQT3

DI - DII

S599

hNav1.5

A572S

LQT3

DI - DII

S599

hNav1.5

A572V

LQT3

DI - DII

S599

hNav1.5

Q573E

LQT3

DI - DII

S600

hNav1.5

G579R

LQT3

DI - DII

S606

hNav1.5

G615E

LQT3

DI - DII

N641

hNav1.5

L619F

LQT3

DI - DII

L615

hNav1.5

P637L

LQT3

DI - DII

hNav1.5

G639R

LQT3

DI - DII

K666

hNav1.5

P648L

LQT3

DI - DII

L675

hNav1.5

E654K

LQT3

DI - DII

N681

hNav1.5

L673P

LQT3

DI - DII

V700

hNav1.5

R680H

LQT3

DI - DII

Q708

hNav1.5

R689C

LQT3

DI - DII

R716

hNav1.5

R689H

LQT3

DI - DII

R716

hNav1.5

P701L

LQT3

DI - DII

P728

hNav1.5

T731I

LQT3

DII S1

T758

hNav1.5

Q750R

LQT3

DII S2

A777

hNav1.5

D772N

LQT3

DII S2-S3

D799

hNav1.5

F816Y

LQT3

DII S4

F843

hNav1.5

I848F

LQT3

DII S5

I875

hNav1.5

S941N

LQT3

DII - DIII

S970

hNav1.5

Q960K

LQT3

DII - DIII

Q989

hNav1.5

R965L

LQT3

DII - DIII

R994

hNav1.5

R971C

LQT3

DII - DIII

N1000

hNav1.5

C981F

LQT3

DII - DIII

hNav1.5

A997S

LQT3

DII - DIII

E1023

hNav1.5

C1004R

LQT3

DII - DIII

Y1037

hNav1.5

E1053K

LQT3

DII - DIII

E1095

hNav1.5

T1069M

LQT3

DII - DIII

D1111

hNav1.5

A1100V

LQT3

DII - DIII

hNav1.5

D1114N

LQT3

DII - DIII

hNav1.5

D1166N

LQT3

DII - DIII

A1153

hNav1.5

R1193Q

LQT3

DII - DIII

N1180

hNav1.5

Y1199S

LQT3

DII - DIII

Y1186

hNav1.5

E1225K

LQT3

DIII S1-S2

E1212

hNav1.5

E1231K

LQT3

DIII S1-S2

R1218

hNav1.5

F1250L

LQT3

DIII S2

F1237

hNav1.5

L1283M

LQT3

DIII S3

L1270

hNav1.5

E1295K

LQT3

DIII S3-S4

D1282

hNav1.5

T1304M

LQT3

DIII S4

T1291

hNav1.5

N1325S

LQT3

DIII S4-S5

N1312

hNav1.5

A1326S

LQT3

DIII S4-S5

A1313

hNav1.5

A1330P

LQT3

DIII S4-S5

A1317

hNav1.5

A1330T

LQT3

DIII S4-S5

A1317

hNav1.5

P1332L

LQT3

DIII S4-S5

P1319

hNav1.5

S1333Y

LQT3

DIII S4-S5

S1320

hNav1.5

I1334V

LQT3

DIII S4-S5

I1321

hNav1.5

L1338V

LQT3

DIII S5

L1325

hNav1.5

R1432S

LQT3

DIII S5-S6

V1419

hNav1.5

S1458Y

LQT3

DIII S6

S1445

hNav1.5

N1472S

LQT3

DIII S6

N1459

hNav1.5

F1473C

LQT3

DIII S6

F1460

hNav1.5

G1481E

LQT3

DIII - DIV

G1468

hNav1.5

F1486L

LQT3

DIII - DIV

F1473

hNav1.5

M1487L

LQT3

DIII - DIV

M1474

hNav1.5

T1488R

LQT3

DIII - DIV

T1475

hNav1.5

E1489D

LQT3

DIII - DIV

E1476

hNav1.5

K1493R

LQT3

DIII - DIV

K1480

hNav1.5

Y1495S

LQT3

DIII - DIV

Y1482

hNav1.5

M1498V

LQT3

DIII - DIV

M1485

hNav1.5

L1501V

LQT3

DIII - DIV

L1488

hNav1.5

K1505N

LQT3

DIII - DIV

K1492

hNav1.5

V1532I

LQT3

DIV S1

I1519

hNav1.5

L1560F

LQT3

DIV S2

L1547

hNav1.5

I1593M

LQT3

DIV S3

I1580

hNav1.5

F1594S

LQT3

DIV S3

F1581

hNav1.5

D1595N

LQT3

DIV S3

D1582

hNav1.5

F1596I

LQT3

DIV S3

F1583

hNav1.5

S1609W

LQT3

DIV S3

A1596

hNav1.5

T1620K

LQT3

DIV S3-S4

T1607

hNav1.5

R1623L

LQT3

DIV S4

R1610

hNav1.5

R1623Q

LQT3

DIV S4

R1610

hNav1.5

R1626H

LQT3

DIV S4

R1613

hNav1.5

R1626P

LQT3

DIV S4

R1613

hNav1.5

R1644C

LQT3

DIV S5

R1631

hNav1.5

R1644H

LQT3

DIV S5

R1631

hNav1.5

T1645M

LQT3

DIV S5

T1632

hNav1.5

L1650F

LQT3

DIV S5

L1637

hNav1.5

M1652R

LQT3

DIV S5

M1639

hNav1.5

M1652T

LQT3

DIV S5

M1639

hNav1.5

I1660V

LQT3

DIV S5

I1647

hNav1.5

V1667I

LQT3

DIV S5

V1654

hNav1.5

T1723N

LQT3

DIV S5-S6

S1710

hNav1.5

R1739W

LQT3

DIV S5-S6

E1727

hNav1.5

L1761F

LQT3

DIV S6

L1749

hNav1.5

L1761H

LQT3

DIV S6

L1749

hNav1.5

V1763M

LQT3

DIV S6

V1751

hNav1.5

M1766L

LQT3

DIV S6

M1754

hNav1.5

Y1767C

LQT3

DIV S6

Y1755

hNav1.5

I1768V

LQT3

DIV S6

I1756

hNav1.5

V1777M

LQT3

C-terminus

V1765

hNav1.5

T1779M

LQT3

C-terminus

T1767

hNav1.5

E1784K

LQT3

C-terminus

E1772

hNav1.5

D1790G

LQT3

C-terminus

D1778

hNav1.5

Y1795C

LQT3

C-terminus

Y1783

hNav1.5

Y1795YD

LQT3

C-terminus

Y1783

hNav1.5

D1819N

LQT3

C-terminus

A1807

hNav1.5

L1825P

LQT3

C-terminus

L1813

hNav1.5

R1826H

LQT3

C-terminus

L1814

hNav1.5

D1839G

LQT3

C-terminus

D1827

hNav1.5

R1897W

LQT3

C-terminus

K1885

hNav1.5

E1901Q

LQT3

C-terminus

E1889

hNav1.5

S1904L

LQT3

C-terminus

S1892

hNav1.5

Q1909R

LQT3

C-terminus

Q1897

hNav1.5

R1913H

LQT3

C-terminus

R1901

hNav1.5

A1949S

LQT3

C-terminus

F1934

hNav1.5

V1951L

LQT3

C-terminus

N1936

hNav1.5

Y1977N

LQT3

C-terminus

Y1958

hNav1.5

F2004L

LQT3

C-terminus

D1982

hNav1.5

F2004V

LQT3

C-terminus

D1982

hNav1.5

R2012C

LQT3

C-terminus

hNav1.5

R18Q

BRGDA1

N-terminus

K17

hNav1.5

R27H

BRGDA1

N-terminus

R26

hNav1.5

N70K

BRGDA1

N-terminus

D65

hNav1.5

D84N

BRGDA1

N-terminus

D79

hNav1.5

F93S

BRGDA1

N-terminus

F88

hNav1.5

I94S

BRGDA1

N-terminus

I89

hNav1.5

V95I

BRGDA1

N-terminus

V90

hNav1.5

R104Q

BRGDA1

N-terminus

R99

hNav1.5

R104W

BRGDA1

N-terminus

R99

hNav1.5

N109K

BRGDA1

N-terminus

P104

hNav1.5

R121Q

BRGDA1

N-terminus

R116

hNav1.5

R121W

BRGDA1

N-terminus

R116

hNav1.5

K126E

BRGDA1

N-terminus

K121

hNav1.5

L136P

BRGDA1

DI S1

L131

hNav1.5

V146M

BRGDA1

DI S1

I141

hNav1.5

E161K

BRGDA1

DI S2

E156

hNav1.5

E161Q

BRGDA1

DI S2

E156

hNav1.5

K175N

BRGDA1

DI S2

K170

hNav1.5

A178G

BRGDA1

DI S2-S3

A173

hNav1.5

C182R

BRGDA1

DI S2-S3

C177

hNav1.5

A185V

BRGDA1

DI S2-S3

E180

hNav1.5

T187I

BRGDA1

DI S3

T182

hNav1.5

A204V

BRGDA1

DI S3

A199

hNav1.5

L212Q

BRGDA1

DI S3-S4

L207

hNav1.5

T220I

BRGDA1

DI S4

T215

hNav1.5

R222Q

BRGDA1

DI S4

R217

hNav1.5

V223L

BRGDA1

DI S4

V218

hNav1.5

R225W

BRGDA1

DI S4

R220

hNav1.5

A226V

BRGDA1

DI S4

A221

hNav1.5

I230V

BRGDA1

DI S4

T225

hNav1.5

V232I

BRGDA1

DI S4

V227

hNav1.5

V240M

BRGDA1

DI S5

V235

hNav1.5

Q270K

BRGDA1

DI S5

Q265

hNav1.5

L276Q

BRGDA1

DI S5-S6

L271

hNav1.5

H278D

BRGDA1

DI S5-S6

H273

hNav1.5

R282C

BRGDA1

DI S5-S6

R277

hNav1.5

R282H

BRGDA1

DI S5-S6

R277

hNav1.5

V294M

BRGDA1

DI S5-S6

I289

hNav1.5

V300I

BRGDA1

DI S5-S6

hNav1.5

L315P

BRGDA1

DI S5-S6

Y304

hNav1.5

G319S

BRGDA1

DI S5-S6

G308

hNav1.5

T320N

BRGDA1

DI S5-S6

S319

hNav1.5

L325R

BRGDA1

DI S5-S6

L314

hNav1.5

P336L

BRGDA1

DI S5-S6

P325

hNav1.5

G351D

BRGDA1

DI S5-S6

G340

hNav1.5

G351V

BRGDA1

DI S5-S6

G340

hNav1.5

T353I

BRGDA1

DI S5-S6

T342

hNav1.5

D356N

BRGDA1

DI S5-S6

D345

hNav1.5

R367C

BRGDA1

DI S5-S6

R356

hNav1.5

R367H

BRGDA1

DI S5-S6

R356

hNav1.5

R367L

BRGDA1

DI S5-S6

R356

hNav1.5

M369K

BRGDA1

DI S5-S6

M358

hNav1.5

W374G

BRGDA1

DI S5-S6

W363

hNav1.5

R376H

BRGDA1

DI S5-S6

N365

hNav1.5

G386E

BRGDA1

DI S5-S6

G375

hNav1.5

G386R

BRGDA1

DI S5-S6

G375

hNav1.5

V396A

BRGDA1

DI S6

V385

hNav1.5

V396L

BRGDA1

DI S6

V385

hNav1.5

N406S

BRGDA1

DI S6

N395

hNav1.5

E439K

BRGDA1

DI - DII

D428

hNav1.5

D501G

BRGDA1

DI - DII

D507

hNav1.5

G514C

BRGDA1

DI - DII

G520

hNav1.5

R526H

BRGDA1

DI - DII

R540

hNav1.5

F532C

BRGDA1

DI - DII

A546

hNav1.5

F543L

BRGDA1

DI - DII

F570

hNav1.5

G552R

BRGDA1

DI - DII

G579

hNav1.5

L567Q

BRGDA1

DI - DII

P594

hNav1.5

G615E

BRGDA1

DI - DII

N641

hNav1.5

L619F

BRGDA1

DI - DII

L615

hNav1.5

R620C

BRGDA1

DI - DII

E647

hNav1.5

T632M

BRGDA1

DI - DII

G659

hNav1.5

P640A

BRGDA1

DI - DII

K667

hNav1.5

A647D

BRGDA1

DI - DII

L674

hNav1.5

P648L

BRGDA1

DI - DII

L675

hNav1.5

R661W

BRGDA1

DI - DII

R688

hNav1.5

H681P

BRGDA1

DI - DII

Q708

hNav1.5

C683G

BRGDA1

DI - DII

C710

hNav1.5

P701L

BRGDA1

DI - DII

P728

hNav1.5

P717L

BRGDA1

DI - DII

P744

hNav1.5

A735E

BRGDA1

DII S1-S2

A762

hNav1.5

A735V

BRGDA1

DII S1-S2

A762

hNav1.5

E746K

BRGDA1

DII S2

K773

hNav1.5

G752R

BRGDA1

DII S2

G779

hNav1.5

G758E

BRGDA1

DII S2

G785

hNav1.5

M764R

BRGDA1

DII S2

M791

hNav1.5

D772N

BRGDA1

DII S2-S3

D799

hNav1.5

P773S

BRGDA1

DII S2-S3

P800

hNav1.5

V789I

BRGDA1

DII S3

V816

hNav1.5

R808P

BRGDA1

DII S4

R835

hNav1.5

R814Q

BRGDA1

DII S4

R841

hNav1.5

L839P

BRGDA1

DII S6

L866

hNav1.5

F851L

BRGDA1

DII S6

F878

hNav1.5

E867Q

BRGDA1

DII S5-S6

E894

hNav1.5

R878C

BRGDA1

DII S5-S6

R907

hNav1.5

R878H

BRGDA1

DII S5-S6

R907

hNav1.5

H886P

BRGDA1

DII S5-S6

H915

hNav1.5

F892I

BRGDA1

DII S5-S6

F921

hNav1.5

R893C

BRGDA1

DII S5-S6

R922

hNav1.5

R893H

BRGDA1

DII S5-S6

R922

hNav1.5

C896S

BRGDA1

DII S5-S6

C925

hNav1.5

E901K

BRGDA1

DII S5-S6

E930

hNav1.5

S910L

BRGDA1

DII S5-S6

A939

hNav1.5

C915R

BRGDA1

DII S5-S6

C944

hNav1.5

L917R

BRGDA1

DII S6

I946

hNav1.5

N927S

BRGDA1

DII S6

N956

hNav1.5

L928P

BRGDA1

DII S6

L957

hNav1.5

L935P

BRGDA1

DII S6

L964

hNav1.5

R965C

BRGDA1

DII - DIII

R994

hNav1.5

R965H

BRGDA1

DII - DIII

R994

hNav1.5

A997T

BRGDA1

DII - DIII

Q1026

hNav1.5

R1023H

BRGDA1

DII - DIII

H1050

hNav1.5

E1053K

BRGDA1

DII - DIII

E1095

hNav1.5

D1055G

BRGDA1

DII - DIII

D1097

hNav1.5

S1079Y

BRGDA1

DII - DIII

hNav1.5

A1113V

BRGDA1

DII - DIII

hNav1.5

S1140T

BRGDA1

DII - DIII

S1128

hNav1.5

R1193Q

BRGDA1

DII - DIII

N1180

hNav1.5

S1219N

BRGDA1

DIII S1

S1206

hNav1.5

E1225K

BRGDA1

DIII S1-S2

E1212

hNav1.5

Y1228H

BRGDA1

DIII S1-S2

Y1215

hNav1.5

R1232Q

BRGDA1

DIII S1-S2

K1219

hNav1.5

R1232W

BRGDA1

DIII S1-S2

K1219

hNav1.5

K1236N

BRGDA1

DIII S2

K1223

hNav1.5

L1339P

BRGDA1

DIII S2

L1226

hNav1.5

E1240Q

BRGDA1

DIII S2

E1227

hNav1.5

D1243N

BRGDA1

DIII S2

D1230

hNav1.5

V1249D

BRGDA1

DIII S2

I1236

hNav1.5

E1253G

BRGDA1

DIII S2

E1240

hNav1.5

G1262S

BRGDA1

DIII S2-S3

G1249

hNav1.5

W1271C

BRGDA1

DIII S3

W1258

hNav1.5

D1275N

BRGDA1

DIII S3

D1262

hNav1.5

A1288G

BRGDA1

DIII S3-S4

A1275

hNav1.5

F1293S

BRGDA1

DIII S3-S4

Y1280

hNav1.5

L1311P

BRGDA1

DIII S4

L1298

hNav1.5

G1319V

BRGDA1

DIII S4-S5

G1306

hNav1.5

V1323G

BRGDA1

DIII S4-S5

V1310

hNav1.5

P1332L

BRGDA1

DIII S4-S5

P1319

hNav1.5

F1344L

BRGDA1

DIII S5

F1331

hNav1.5

F1344S

BRGDA1

DIII S5

F1331

hNav1.5

L1346I

BRGDA1

DIII S5

L1333

hNav1.5

L1346P

BRGDA1

DIII S5

L1333

hNav1.5

M1351R

BRGDA1

DIII S5

M1338

hNav1.5

V1353M

BRGDA1

DIII S5

V1340

hNav1.5

G1358W

BRGDA1

DIII S5-S6

G1345

hNav1.5

K1359N

BRGDA1

DIII S5-S6

K1346

hNav1.5

F1360C

BRGDA1

DIII S5-S6

F1347

hNav1.5

C1363Y

BRGDA1

DIII S5-S6

C1350

hNav1.5

S1382I

BRGDA1

DIII S5-S6

E1369

hNav1.5

V1405L

BRGDA1

DIII S5-S6

V1392

hNav1.5

V1405M

BRGDA1

DIII S5-S6

V1392

hNav1.5

G1406E

BRGDA1

DIII S5-S6

G1393

hNav1.5

G1406R

BRGDA1

DIII S5-S6

G1393

hNav1.5

G1408R

BRGDA1

DIII S5-S6

G1395

hNav1.5

Y1409C

BRGDA1

DIII S5-S6

Y1396

hNav1.5

L1412F

BRGDA1

DIII S5-S6

L1399

hNav1.5

K1419E

BRGDA1

DIII S5-S6

K1406

hNav1.5

G1420R

BRGDA1

DIII S5-S6

G1407

hNav1.5

A1427S

BRGDA1

DIII S5-S6

A1414

hNav1.5

A1428V

BRGDA1

DIII S5-S6

A1415

hNav1.5

R1432G

BRGDA1

DIII S5-S6

V1419

hNav1.5

R1432S

BRGDA1

DIII S5-S6

V1419

hNav1.5

G1433V

BRGDA1

DIII S5-S6

N1420

hNav1.5

P1438L

BRGDA1

DIII S5-S6

P1425

hNav1.5

E1441Q

BRGDA1

DIII S5-S6

E1428

hNav1.5

I1448L

BRGDA1

DIII S6

I1435

hNav1.5

I1448T

BRGDA1

DIII S6

I1435

hNav1.5

Y1449C

BRGDA1

DIII S6

Y1436

hNav1.5

V1451D

BRGDA1

DIII S6

V1438

hNav1.5

N1463Y

BRGDA1

DIII S6

N1450

hNav1.5

V1468F

BRGDA1

DIII S6

V1455

hNav1.5

Y1494N

BRGDA1

DIII - DIV

Y1481

hNav1.5

L1501V

BRGDA1

DIII - DIV

L1488

hNav1.5

G1502S

BRGDA1

DIII - DIV

G1489

hNav1.5

R1512W

BRGDA1

DIII - DIV

R1499

hNav1.5

I1521K

BRGDA1

DIII - DIV

I1508

hNav1.5

V1525M

BRGDA1

DIII - DIV

V1512

hNav1.5

K1527R

BRGDA1

DIII - DIV

N1514

hNav1.5

E1548K

BRGDA1

DIV S1-S2

E1535

hNav1.5

A1569P

BRGDA1

DIV S2

I1556

hNav1.5

F1571C

BRGDA1

DIV S2

F1558

hNav1.5

E1574K

BRGDA1

DIV S2

E1561

hNav1.5

L1582P

BRGDA1

DIV S2-S3

L1569

hNav1.5

R1583C

BRGDA1

DIV S2-S3

R1570

hNav1.5

R1583H

BRGDA1

DIV S2-S3

R1570

hNav1.5

V1604M

BRGDA1

DIV S3

V1591

hNav1.5

Q1613L

BRGDA1

DIV S3-S4

E1600

hNav1.5

T1620M

BRGDA1

DIV S3-S4

T1607

hNav1.5

R1623Q

BRGDA1

DIV S4

R1610

hNav1.5

R1629Q

BRGDA1

DIV S4

R1616

hNav1.5

G1642E

BRGDA1

DIV S5

G1629

hNav1.5

R1644C

BRGDA1

DIV S5

R1631

hNav1.5

A1649V

BRGDA1

DIV S5

A1636

hNav1.5

I1660V

BRGDA1

DIV S5

I1647

hNav1.5

G1661R

BRGDA1

DIV S5

G1648

hNav1.5

V1667I

BRGDA1

DIV S5

V1654

hNav1.5

S1672Y

BRGDA1

DIV S5

A1659

hNav1.5

A1680T

BRGDA1

DIV S5-S6

A1667

hNav1.5

A1698T

BRGDA1

DIV S5-S6

G1685

hNav1.5

T1709M

BRGDA1

DIV S5-S6

T1696

hNav1.5

T1709R

BRGDA1

DIV S5-S6

T1696

hNav1.5

G1712S

BRGDA1

DIV S5-S6

G1699

hNav1.5

D1714G

BRGDA1

DIV S5-S6

D1701

hNav1.5

N1722D

BRGDA1

DIV S5-S6

N1709

hNav1.5

C1728R

BRGDA1

DIV S5-S6

C1715

hNav1.5

C1728W

BRGDA1

DIV S5-S6

C1715

hNav1.5

G1740R

BRGDA1

DIV S5-S6

G1728

hNav1.5

G1743E

BRGDA1

DIV S5-S6

G1731

hNav1.5

G1743R

BRGDA1

DIV S5-S6

G1731

hNav1.5

V1764F

BRGDA1

DIV S6

V1752

hNav1.5

T1779M

BRGDA1

C-terminus

T1767

hNav1.5

E1784K

BRGDA1

C-terminus

E1772

hNav1.5

Y1795H

BRGDA1

C-terminus

Y1783

hNav1.5

Y1795YD

BRGDA1

C-terminus

Y1783

hNav1.5

Q1832E

BRGDA1

C-terminus

K1820

hNav1.5

C1850S

BRGDA1

C-terminus

C1838

hNav1.5

V1861I

BRGDA1

C-terminus

V1849

hNav1.5

K1872N

BRGDA1

C-terminus

R1860

hNav1.5

V1903L

BRGDA1

C-terminus

V1891

hNav1.5

A1924T

BRGDA1

C-terminus

I1912

hNav1.5

G1935S

BRGDA1

C-terminus

G1920

hNav1.5

E1938K

BRGDA1

C-terminus

D1923

hNav1.5

V1951L

BRGDA1

C-terminus

N1936

hNav1.5

I1968S

BRGDA1

C-terminus

T1949

hNav1.5

F2004L

BRGDA1

C-terminus

D1982

hNav1.5

F2004V

BRGDA1

C-terminus

D1982

hNav1.5

T220I

SSS1

DI S4

T215

hNav1.5

A735V

SSS1

DII S1-S2

A762

hNav1.5

P1298L

SSS1

DIII S3-S4

P1285

hNav1.5

G1408R

SSS1

DIII S5-S6

G1395

hNav1.5

D1792N

SSS1

C-terminus

E1780

hNav1.5

S1710L

VF1

DIV S5-S6

S1697

hNav1.5

F532C

SIDS

DI - DII

F557

hNav1.5

S941N

SIDS

DII - DIII

S970

hNav1.5

G1084S

SIDS

DII - DIII

hNav1.5

S1333Y

SIDS

DIII S4-S5

S1320

hNav1.5

F1705S

SIDS

DIV S5-S6

F1692

hNav1.5

D1275N

ATRST1

DIII S3

D1262

hNav1.5

D1275N

CMD1E

DIII S3

D1262

hNav1.5

M138I

ATFB10

DI S1

M133

hNav1.5

E428K

ATFB10

DI - DII

K417

hNav1.5

H445D

ATFB10

DI - DII

Q434

hNav1.5

N470K

ATFB10

DI - DII

S472

hNav1.5

A572D

ATFB10

DI - DII

S599

hNav1.5

E655K

ATFB10

DI - DII

D682

hNav1.5

E1053K

ATFB10

DII - DIII

E1095

hNav1.5

T1131I

ATFB10

DII - DIII

E1140

hNav1.5

R1826C

ATFB10

C-terminus

L1814

hNav1.5

V1951M

ATFB10

C-terminus

N1936

hNav1.5

N1987K

ATFB10

C-terminus

E1967

hNav1.5

R222Q

MEPPC

DI S4

R217

PFHB1A: Progressive familial heart block 1A; LQT3: Long QT syndrome 3; BRGDA1: Brugada syndrome 1; SSS1: Sick sinus syndrome 1; VF1: Familial paroxysmal ventricular fibrillation 1; SIDS: Sudden infant death syndrome; ATRST1: Atrial standstill 1; CMD1E: Cardiomyopathy, dilated 1E; ATFB10: Atrial fibrillation, familial, 10; MEPPC: Multifocal ectopic Purkinje-related premature contraction

Table 7

Structural mapping of disease-related mutations identified in human Nav1.6

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.6

D58N

EIEE13

N-terminus

D52

hNav1.6

F210L

EIEE13

DI S3-S4

F204

hNav1.6

G214D

EIEE13

DI S3-S4

G208

hNav1.6

N215R

EIEE13

DI S3-S4

N209

hNav1.6

V216D

EIEE13

DI S3-S4

V210

hNav1.6

R223G

EIEE13

DI S4

R217

hNav1.6

F260S

EIEE13

DI S5

F254

hNav1.6

L407F

EIEE13

DI S6

L398

hNav1.6

V410L

EIEE13

DI - DII

V401

hNav1.6

E479V

EIEE13

DI - DII

E464

hNav1.6

R530W

EIEE13

DI - DII

H515

hNav1.6

R662C

EIEE13

DI - DII

Q643

hNav1.6

T767I

EIEE13

DII S1

T758

hNav1.6

F846S

EIEE13

DII S4

F837

hNav1.6

R850Q

EIEE13

DII S4

R841

hNav1.6

L875Q

EIEE13

DII S5

L866

hNav1.6

A890T

EIEE13

DII S5

A881

hNav1.6

V960D

EIEE13

DII S6

V951

hNav1.6

N984K

EIEE13

DII - DIII

N975

hNav1.6

I1327V

EIEE13

DIII S4-S5

I1321

hNav1.6

L1331V

EIEE13

DIII S5

L1325

hNav1.6

G1451S

EIEE13

DIII S6

G1444

hNav1.6

G1451S

EIEE13

DIII S6

G1444

hNav1.6

N1466K

EIEE13

DIII S6

N1459

hNav1.6

N1466T

EIEE13

DIII S6

N1459

hNav1.6

I1479V

EIEE13

DIII - DIV

I1472

hNav1.6

E1483K

EIEE13

DIII - DIV

E1476

hNav1.6

I1583T

EIEE13

DIV S2-S3

V1576

hNav1.6

V1592L

EIEE13

DIV S3

V1585

hNav1.6

S1596C

EIEE13

DIV S3

S1589

hNav1.6

I1605R

EIEE13

DIV S3

L1598

hNav1.6

R1617Q

EIEE13

DIV S4

R1610

hNav1.6

L1621W

EIEE13

DIV S4

L1614

hNav1.6

A1650T

EIEE13

DIV S5

A1643

hNav1.6

P1719R

EIEE13

DIV S5-S6

P1713

hNav1.6

N1768D

EIEE13

DIV S6

N1762

hNav1.6

Q1801E

EIEE13

C-terminus

Q1795

hNav1.6

E1870D

EIEE13

C-terminus

E1864

hNav1.6

R1872W

EIEE13

C-terminus

R1866

hNav1.6

R1872Q

EIEE13

C-terminus

R1866

hNav1.6

R1872L

EIEE13

C-terminus

R1866

hNav1.6

N1877S

EIEE13

C-terminus

N1871

EIEE13: Epileptic encephalopathy, early infantile, 13

Table 8

Structural mapping of disease-related mutations identified in human Nav1.8

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.8

L554P

SFN

DI - DII

hNav1.8

M650K

SFN

DI - DII

Y729

hNav1.8

A1304T

SFN

DIII S5

A1344

hNav1.8

G1662S

SFN

DIV S5-S6

G1699

hNav1.8

I1706V

SFN

DIV S6

I1744

SFN: Small fiber neuropathy

Table 9

Structural mapping of disease-related mutations identified in human Nav1.9

Related proteins

Mutations

Diseases

Structural position

Map on hNav1.7

hNav1.9

R222H

FEPS3

DI S4

R214

hNav1.9

R222S

FEPS3

DI S4

R214

hNav1.9

R225C

FEPS3

DI S4

R217

hNav1.9

I381T

FEPS3

DI S6

V383

hNav1.9

G699R

FEPS3

DII S5

G864

hNav1.9

A808G

FEPS3

DII S6

A965

hNav1.9

L811P

HSAN7

DII S6

L968

hNav1.9

L1158P

FEPS3

DIII S4

L1301

hNav1.9

V1184A

HSAN7

DIII S5

V1327

FEPS3: Episodic pain syndrome, familial, 3; HSAN7: Neuropathy, hereditary sensory and autonomic, 7

Table 10

Summary of sodium channelopathies

Related proteins

Diseases

hNav1.1

GEFS+2: Generalized epilepsy with febrile seizures plus 2

EIEE6: Epileptic encephalopathy, early infantile, 6

ICEGTC: Intractable childhood epilepsy with generalized tonic-clonic seizures

FHM3: Migraine, familial hemiplegic, 3

FEB3A: Febrile seizures, familial, 3A

hNav1.2

BFIS3: Seizures, benign familial infantile 3

EIEE11: Epileptic encephalopathy, early infantile, 11

DS: Dravet syndrome

hNav1.3

CPE: Cryptogenic partial epilepsy

hNav1.4

PMC: Paramyotonia congenita of von Eulenburg

HOKPP2: Periodic paralysis hypokalemic 2

HYPP: Periodic paralysis hyperkalemic

NKPP: Periodic paralysis normokalemic

MYOSCN4A: Myotonia SCN4A-related

CMS16: Myasthenic syndrome, congenital, 16

hNav1.5

PFHB1A: Progressive familial heart block 1A

LQT3: Long QT syndrome 3

BRGDA1: Brugada syndrome 1

SSS1: Sick sinus syndrome 1

VF1: Familial paroxysmal ventricular fibrillation 1

SIDS: Sudden infant death syndrome

ATRST1: Atrial standstill 1

CMD1E: Cardiomyopathy, dilated 1E

ATFB10: Atrial fibrillation, familial, 10

MEPPC: Multifocal ectopic Purkinje-related premature contraction

hNav1.6

EIEE13: Epileptic encephalopathy, early infantile, 13

hNav1.7

IEM: Primary erythermalgia

PEPD: Paroxysmal extreme pain disorder

CIP: Indifference to pain, congenital, autosomal recessive

DS: Dravet syndrome

SFN: Small fiber neuropathy

FEB: Febrile eizures

hNav1.8

SFN: Small fiber neuropathy

hNav1.9

FEPS3: Episodic pain syndrome, familial, 3

HSAN7: Neuropathy, hereditary sensory and autonomic, 7

Despite significant advancement in the understanding of Nav channel functions and their relevance to diseases, structural characterization of mammalian Nav channels at atomic level has been challenging, partly due to the substantial technical hurdles in producing mammalian Nav channel proteins in sufficient amount with acceptable purity. The two published bacterial Nav channel crystal structures, NavAb (Payandeh et al., 2011) and NavRh (Zhang et al., 2012), in their full-length have greatly improved our understanding of how those channels conduct and select sodium ions on a structural basis. This is further enhanced by the recently published cryo-electron microscopy (cryo-EM) structure of the rabbit voltage-gated calcium (Cav) channel Cav1.1 (Wu et al., 2015; Wu et al., 2016), which, given the significant similarities between Cav and Nav channels, provides an excellent base model for studying the structure and function of the mammalian Nav channels in lieu of the elusive Nav channel structure (Wu et al., 2015; Wu et al., 2016). In this Resource article, we have built a structure model of the human sodium channel Nav1.7 based on the Cav1.1 cryo-EM structure (PDB code: 5GJV). Disease-related mutations of various Nav channels are systematically mapped onto this Nav1.7 structural model. As expected, most mutations are located in the VSDs and the pore domain, which corroborate the functional disturbance associated with the various conditions. The human Nav1.7 structure model may also provide a useful tool for the structure-based design of drugs that are able to therapeutically target the Nav channels.

STRUCTURE MODEL OF HUMAN SODIUM CHANNEL Nav1.7

Homology models of the mammalian Nav channels have been previously constructed based on the crystal structures of the eukaryotic potassium channels or the prokaryotic sodium channels (Tikhonov and Zhorov, 2012; Yang et al., 2012). However, the relevance of such models has been in question, since the eukaryotic sodium channels are known to be heterotetrameric while the prokaryotic sodium channels and the potassium channels are of homotetrameric nature.

We sought to build a homology-based structural model for human Nav1.7 because of the tremendous interest in drug development targeting this channel. The sequence identity and similarity between human Nav1.7 and rabbit Cav1.1 are 21 and 35%, respectively (Please refer to the online Supplementary Fig. 2 of Wu et al., 2016). Importantly, the key amino acids within the VSDs and the pore domains are highly conserved (Wu et al., 2015; Wu et al., 2016). The cryo-EM structure of rabbit Cav1.1 was then used as the template for homology modeling of human Nav1.7. The primary sequence of human Nav1.7 was aligned with rabbit Cav1.1 in MOE with manual adjustment when necessary. The structure model of human Nav1.7 was created with the Homology Model module in MOE using the GB/VI scoring function with AMBER12:EHT force field (MOE, 2016).

The human Nav1.7 model structure resembles the structure of rCav1.1 in general (Fig. 1A). However, the model exhibits pronounced differences from the calcium channel and bacterial sodium channels particularly in selectivity filter. The SF of Nav1.7 consists of four different amino acid residues DEKA (Fig. 1B). In contrast, the Cav1.1 SF is constituted by four repeated essential glutamic acids, EEEE, while NavAb and NavRh contain TLESWS or TLSSWE in each protomer, respectively. This human Nav1.7 structure model represents the first one-chain sodium channel model with asymmetric repeats and is expected to shed new light on the mammalian sodium channel functions.
Figure 1

Homology model structure of human Nav1.7 sodium channel. (A) Intra-membrane view and extracellular view of the structure model of Nav1.7. The four domains are colored green, light blue, cyan, and gray for domain I, II, III, and IV, respectively. (B) The pore domain of Nav1.7 structure model. The S5–S6 segments of Nav1.7 are shown and the four selectivity filter amino acids are shown as sticks (left). A close-up view of the four SF residues, D361 in domain I, E927 in domain II, K1406 in domain III, and A1698 in domain IV (right)

MAPPING OF DISEASE-RELEVANT MUTATIONS ONTO THE Nav1.7 STRUCTURE MODEL

Human Nav1.7 sodium channel is preferentially expressed in the sensory neurons of dorsal root ganglia and sympathetic ganglia neurons, particularly within the nociceptors, which is essential for perceiving pain (Djouhri et al., 2003; Dib-Hajj et al., 2013). To date, about 60 mutations of Nav1.7 have been found to cause human pain syndromes including IEM, PEPD, CIP, SFN (small fiber neuropathy), DS (Dravet syndrome), and FEB (febrile seizure) (Fig. 2 and Table 1). We mapped all the reported Nav1.7 mutations onto this Nav1.7 structure model (Fig. 2). Nineteen out of 22 IEM mutations are located in the highly conserved regions of VSDs and the pore domain except for the Q10R, P610T, and G616R mutations (Fig. 2). Electrophysiology study showed that IEM mutations cause a prominent shift of the activation voltage toward a more negative region or delay deactivation, which results in neuron hyperexcitability (Choi et al., 2006; Lampert et al., 2006; Choi et al., 2009; Lampert et al., 2010). For example, mutation of A1643 within the S5 segment of domain IV to glycine (A1643G) generates a significant hyperpolarizing shift (Yang et al., 2016). Our structural analysis shows that only two IEM mutations F216S and L834R are located in the S4 positively charged segment that is directly responsible for transmembrane voltage sensing and channel activation. How other IEM mutations influence voltage sensing and channel functions is yet to be elucidated.
Figure 2

Amino acid locations of Nav1.7 disease-related mutations on the Nav1.7 structure model. (A) The topology of human Nav1.7 sodium channel. Cylinders represent the transmembrane segments, which are colored in gray except that the S4 voltage-sensing segments are colored in yellow. The lines represent the soluble regions between the transmembrane segments or the N/C-terminus. The two P helices between S5 and S6 segments are shown in cylinders. Mutations of Nav1.7 are discriminately mapped on the topology scheme of Nav1.7 by different colors, namely, IEM (blue), PEPD (red), CIP (cyan), DS (purple), SFN (green), and FEB (pink). (B) Intra-membrane view and intracellular views of the Nav1.7 structure model. Mapping of disease-related mutations onto the Nav1.7 structure model is highlighted by different colors. Summary of Nav1.7 mutations is shown in different gray boxes

The PEPD mutations are mostly characterized (nine out of 11) within the S4 segment, S4-S5 linker region, and the cytosolic regions of domain III and domain IV of Nav1.7 except for R185H and R1007C (Fig. 2A and Table 1). Specifically, I1472T, F1473V, and T1475I are within the IFMT motif (Fig. 2A), indicating that they may disturb channel inactivation. Indeed, IFMT mutations usually impair fast inactivation with consequently persistent currents (Fertleman et al., 2006). The V1309D, V1309F, and V1310F mutations are located in the S4-S5 linker region of domain III and they have been shown to cause moderate destabilization of fast inactivation (Jarecki et al., 2008). The G1618R mutation, located within the S4 segment of domain IV, impairs inactivation and retains a persistent current compared to the wild-type (WT) channel (Choi et al., 2011), while another domain IV S4 segment mutation, L1623P, significantly increases ramp current and shortens recovery time from inactivation (Suter et al., 2015). Moreover, electrophysiology study showed that M1638K mutation (within the S5 segment of domain IV) generates faster recovery from inactivation than the WT channel, producing greater currents and reducing the threshold with increased number of action potentials (Fertleman et al., 2006; Dib-Hajj et al., 2008). Another PEPD mutation, A1643E, also located in the S5 segment of domain IV, impedes channel full inactivation, which results in persistent inward currents (Estacion et al., 2008).

The CIP patients, characterized by lack of nociceptive perception, are mostly inflicted by Nav1.7 nonsense mutations, which result in premature protein truncations and inability to produce functional sodium channels. Only three mutations of Nav1.7, namely R907Q, A1247E, and W1786R, have been reported to be associated with CIP (Fig. 2 and Table 1). Diseases such as DS, SFN, and FEB are also known to be caused by Nav1.7 mutations (Fig. 2 and Table 1). For example, all eight SFN mutations have been characterized. Specifically, I228M, I731K, I750V, and M1543I mutations impair slow inactivation, D623N impedes slow and fast inactivation, while R185H, M943L, and V1002L mutations enhance resurgent currents (Faber et al., 2012a). On the other hand, Nav1.7 mutations that are associated with DS (nine mutations) and FEB (six mutations) have not been well characterized.

MAPPING OF OTHER HUMAN SODIUM CHANNEL DISEASE-RELATED MUTATIONS ONTO THE Nav1.7 STRUCTURE MODEL

Members of the human Nav channel family share high sequence similarity and mutations of these Nav channels are known to cause a vast variety of channelopathies. In order to better understand the role of those mutations in disturbing normal channel functions on a structural level, we mapped the disease-related mutations of other human Nav channels onto the Nav1.7 structure model based on the sequence alignment reported in Wu et al., 2016 (Fig. 3).
Figure 3

Mapping of Nav channel disease-related mutations onto the Nav1.7 structure model. The Nav1.7 channel is shown in cartoon from the intra-membrane view. The Cα atoms of the disease-related amino acids are shown in spheres. Mapped mutations from nine Nav sodium channels to the Nav1.7 structure model are differentiated by distinct colors, Nav1.1 (A, blue), Nav1.2 (B, cyan), Nav1.3 (C, magenta), Nav1.4 (D, purple blue), Nav1.5 (E, pale cyan), Nav1.6 (F, orange), Nav1.7 (G, red), Nav1.8 (H, green), and Nav1.9 (I, salmon)

Among all the nine Nav channels, Nav1.1 and Nav1.5 have the largest numbers of reported mutations (more than 400 each) (Fig. 3A and 3E), while Nav1.3, Nav1.8, and Nav1.9 have the least numbers (less than 10 each) (Fig. 3C, 3H, and 3I). Notably, mutations in Nav1.1, Nav1.2, Nav1.3, and Nav1.6 mainly cause epilepsies; those in Nav1.4 are related to myopathies; in Nav1.5 result in cardiac channelopathies; and in Nav1.7, Nav1.8, and Nav1.9 are associated with pain-related diseases (Fig. 3 and Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Mapping of all Nav channel mutations onto the Nav1.7 structure model revealed that more than 80% of mutations are located in the VSDs and pore domains (Fig. 4A and 4B). Notably, disease-causing mutations are somewhat equally distributed in all four Nav channel domains, which account for more than 20 sodium channelopathies (Fig. 4C). Furthermore, mutations are also distributed in various regions of the pore domains, suggesting that they may disturb Nav channel functions by altering sodium ion selectivity and conductivity (Fig. 4D).
Figure 4

Mutations that cause sodium channelopathies are plotted on the Nav1.7 sodium channel model. (A) The amino acid residues related with sodium channelopathies are mapped on the Nav1.7 structure model. All mutated residues are shown in spheres and colored for Nav1.1 (blue), Nav1.2 (cyan), Nav1.3 (magenta), Nav1.4 (purple blue), Nav1.5 (pale cyan), Nav1.6 (orange), Nav1.7 (red), Nav1.8 (green), and Nav1.9 (salmon). (B) The distribution of sodium channelopathy-related mutations on the transmembrane regions of the Nav1.7 structure model. Mutations of the VSDs and the pore domain are shown from the intra-membrane and intracellular views. (C) The mutation distributions for the four domains. S1–S6 segments are shown in cylindrical helices. (D) Mapping mutations to the pore domain in four different views

Nav1.2 mutations are largely associated with various epilepsy diseases, including BFIS3 (seizures, benign familial infantile 3), EIEE11 (epileptic encephalopathy, early infantile, 11), and DS (Fig. 3B and Table 3). More than 30 Nav1.2 mutations have been discovered and some of them are now functionally characterized. Interestingly, electrophysiological studies showed that Nav1.2 mutations can either be loss-of-function (R1319Q and L1330F) or gain-of-function (M252V, V261M, L1563V, and Y1579C) (Misra et al., 2008; Liao et al., 2010; Lauxmann et al., 2013). It is noted that BFIS3 mutations in Nav1.2 create less pronounced changes in the activation and inactivation potentials than the EIEE11 mutations (Shi et al., 2012).

Only six missense mutations of Nav1.3 have so far been identified in patients with cryptogenic partial epilepsy (Fig. 3C and Table 4). Five of them, namely K354Q, R357Q, D815N, E1160K, and M1372V, have been characterized, all of which are gain-of-function mutations, consistent with the neuronal hyperexcitability phenotype (Estacion et al., 2010; Vanoye et al., 2014).

Nav1.4 is essential for controlling the muscle action potential and consequently crucial for skeletal muscle contraction. Mutations of Nav1.4 are related with various neuromuscular disorders including PMC (paramyotonia congenita of von Eulenburg), HOKPP2 (periodic paralysis hypokalemic 2), HYPP (periodic paralysis hyperkalemic), NKPP (periodic paralysis normokalemic), MYOSCN4A (myotonia SCN4A-related), and CMS16 (myasthenic syndrome, congenital, 16) (Fig. 3D and Table 5). Different disease-causing mutations alter the Nav1.4 channel function through distinct mechanisms. For example, CMS16 mutations R104H, P382T, and C1209F completely abolish the Nav1.4 channel’s ability to conduct sodium ion, while other mutations such as M203K, R225W, and D1069N cause reduced action potential amplitude, leading to impaired channel function (Zaharieva et al., 2016). Compared to the WT channel, a CMS16 voltage sensor mutant R1457H requires longer hyperpolarization to recover which results in increased fast inactivation (Arnold et al., 2015). On the other hand, a HOKPP2 mutation R1135H (the third arginine in the domain III voltage sensor) exhibits increased depolarization, suggesting that R1135H mutation be gain-of-function (Groome et al., 2014). A MYOSCN4A mutation I582V shows a hyperpolarizing shift of 6 mV, indicating the nature of this mutation be also gain-of-function (Corrochano et al., 2014).

Nav1.6 is one of the sodium channels expressed in human brain and mutations of Nav1.6 cause EIEE13 (epileptic encephalopathy, early infantile, 13) (Fig. 3F and Table 7). More than 40 Nav1.6 mutations have been discovered since 2012 (Fig. 3F and Table 7), and seven of them have been studied in the functional assays. Specifically, five Nav1.6 mutations, namely T767I, N984K, T1716I, N1768D, and R1872W/R1872Q/R1872L, are characterized as gain-of-function, which cause hyperpolarizing shift of inactivation voltage or increased persistent current (Veeramah et al., 2012; Estacion et al., 2014; Wagnon et al., 2016), while the other two mutations, R223G and G1451S, are loss-of-function (de Kovel et al., 2014; Blanchard et al., 2015).

Five Nav1.8 mutations are associated with SFN, a condition that is clinically characterized by autonomic dysfunction and burning pain in the distal extremities (Fig. 3H and Table 8). Electrophysiology study has shown that Nav1.8 mutations, specifically L554P, A1304T, G1662S, and I1706V, accelerate inactivation recovery and enhance activation, which result in hyperexcitability (Faber et al., 2012b; Huang et al., 2013; Han et al., 2014). However, another SFN Nav1.8 mutation M650K causes reduced excitability of C fibers (Kist et al., 2016).

FEPS3 (episodic pain syndrome, familial, 3) and HSAN7 (neuropathy, hereditary sensory and autonomic, 7) are thought to be caused by the nine missense gain-of-function mutations of Nav1.9 (Fig. 3I and Table 9). Specifically, compared to the WT channel, R225C and A808G mutations induce hyperexcitability of the DRG neurons (Zhang et al., 2013), G699R enhances activation (Han et al., 2015), L811P significantly increases current density (Leipold et al., 2013), L1158P enhances spontaneous firing (Huang et al., 2014), and V1184A alters the channel voltage dependence that results in channel opening in response to hyperpolarized potentials (Leipold et al., 2015).

DISEASE-RELATED MUTATIONS IN SODIUM CHANNELS Nav1.1 AND Nav1.5

Mutations of Nav1.1 are associated with several neurological disorders including GEFS+2, EIEE6, ICEGTC, FHM3 (migraine, familial hemiplegic, 3), and FEB3A (febrile seizures, familial, 3A) (Table 2 and Table 10). More than 400 mutations of Nav1.1 have been identified, approximately 10% account for GEFS+2 while 80% for EIEE6 (Fig. 5A and Table 2). By mapping the Nav1.1-related mutations to the Nav1.7 structure model, we identified that most mutations are located in the VSDs and the pore domain (Fig. 5A). For example, mutations of the four positively charged residues, R1639G, R1642S, R1645Q, and R1648C, are present in the domain IV S4 segment (Table 2), suggesting that these EIEE6 mutations may alter the voltage sensing behavior of the channel. In addition, it is noteworthy that Nav1.1 mutations can be either loss-of-function or gain-of-function (Catterall et al., 2010; Escayg and Goldin, 2010). For example, two GEFS+2 mutations W1204R and R1648H increase the level of persistent current through gain-of-function (Lossin et al., 2002), while the loss-of-function M145T mutation in FEB3A decreases 60% of the current density (Mantegazza et al., 2005).
Figure 5

Distributions of the missense mutations in Nav1.1 and Nav1.5. (A) Distributions of Nav1.1 missense mutations on the Nav1.7 model structure. More than 400 mutations are mapped. Mutations from five Nav1.1-related diseases are shown from intra-membrane, intracellular, and extracellular views. The Nav1.7 model is shown in cylindrical helices and colored by GEFS+2 in red, EIEE6 in blue, ICEGTC in cyan, FHM3 in green, and FEB3A in yellow. (B) Distributions of Nav1.5 related-disease mutations on the Nav1.7 structure model. Mutations from Nav1.5 related diseases are shown from intra-membrane, intracellular, and extracellular views. Different diseases are colored in green for PFHB1A, blue for LQT3, red for BRGDA1, cyan for SSS1, and magenta for VF1, SIDS, ATRST1, CMD1E, ATFB10, and MEPPC

Nav1.5 is the primary sodium channel in the heart and is essential for the cardiac action potential initiation. More than 400 Nav1.5 mutations have been discovered and they are implicated in a wide variety of cardiac diseases—including PFHB1A (progressive familial heart block 1A), LQT3, BRGDA1, SSS1, VF1 (familial paroxysmal ventricular fibrillation 1), SIDS (sudden infant death syndrome), ATRST1 (atrial standstill 1), CMD1E (cardiomyopathy, dilated 1E), ATFB10 (atrial fibrillation, familial, 10), and MEPPC (multifocal ectopic Purkinje-related premature contractions) (Fig. 5B and Table 6). By mapping all the Nav1.5 mutations onto the Nav1.7 structure model, it shows that most mutations are located in the transmembrane regions of the channel, suggesting that these mutations might disturb voltage sensing or sodium conduction (Fig. 5B). Furthermore, about 50% of the Nav1.5 mutations account for BRGDA1, while 30% for LQT3. Similar to the case of Nav1.1, mutations in Nav1.5 can be either loss-of-function or gain-of-function. For example, loss-of-function mutations are associated with BRGDA1, CMD1E, SSS1, and ATFB10 (Tan et al., 2001; Smits et al., 2005; Makiyama et al., 2008; Laurent et al., 2012), while gain-of-function mutations of Nav1.5 are responsible for LQT3 (Remme et al., 2006), CMD1E, and ATFB10 (Olson et al., 2005), and most recently MEPPC (Swan et al., 2014).

CONCLUDING REMARKS

The Nav family of sodium channels are important drug targets for the pharmaceutical industry. However, no atomic structure of any mammalian Nav channels is currently available, preventing the establishment of an in-depth structure-function relationship for this important group of sodium channels and application of structure-based approach to rationally design compounds that are able to modulate the functions of those Nav channels in a disease relevant manner. Using the recently published cryo-EM structure of a rabbit Cav channel Cav1.1, we established an atomic level heterotetrameric structure model for the human Nav channel Nav1.7. Disease-related mutations of Nav1.7 and other members of the Nav family, which are largely responsible for many neurological disorders like epilepsies, pains, and myopathies, are mapped onto the structure model. Taken together the available functional data, we attempted to establish a rudimentary structure-function relationship for human Nav1.7 and other members of the Nav channel family. It is noticeable that sodium channelopathies can be attributed to both loss-of-function and gain-of-function mutations.

However, we must realize that the current Nav1.7 structural model has its limitation and the atomic resolution mammalian Nav channel structure is urgently needed. In recent years, cryo-EM technology is becoming a mainstream technology for structural biology, which is able to potentially overcome the significant technical hurdles in producing challenging proteins such as mammalian Nav channels in sufficient quality and the necessity of crystallization for structural elucidation. Detailed mechanisms of how the Nav channels sense voltage changes and conduct sodium ions can only be answered when such atomic resolution structures become available. We hope the Nav1.7 structure model presented here is a temporary surrogate to help understand the Nav channel functions, particularly those relevant to the various neurological diseases, at atomic level, and contributes to the structure-based rational design of the next generation Nav channel modulators.

SUMMARY OF DISEASE-RELATED MUTATIONS FOR SODIUM CHANNELS

Most of the Nav channel disease-related mutations are extracted from the UNIPROT websites:

http://www.uniprot.org/uniprot/P35498 (Nav1.1);

http://www.uniprot.org/uniprot/Q99250 (Nav1.2);

http://www.uniprot.org/uniprot/P35499 (Nav1.4);

http://www.uniprot.org/uniprot/Q14524 (Nav1.5);

http://www.uniprot.org/uniprot/Q9UQD0 (Nav1.6);

http://www.uniprot.org/uniprot/Q15858 (Nav1.7);

http://www.uniprot.org/uniprot/Q9Y5Y9 (Nav1.8);

http://www.uniprot.org/uniprot/Q9UI33 (Nav1.9).

In the UNIPROT websites, there are no mutations described for Nav1.3. During literatures searching, we found that six mutations of Nav1.3 are associated with cryptogenic partial epilepsy. Except for the present mutations in the UNIPROT websites, we found additional mutations of Nav channels in literatures. All mutations are summarized in Tables 1, 2, 3, 4, 5, 6, 7, 8, 9. However, we recognize that our summary may not contain all Nav channel disease-related mutations owing to abundant literatures reporting Nav channel disease-related mutations and increasing volume of work describing new findings.

Notes

ACKNOWLEDGEMENTS

This work was supported by funds from the National Basic Research Program (973 Program) (2015CB910101, 2016YFA0500402, 2014ZX09507003-006), the National Natural Science Foundation of China (projects 31621092, 31630017, and 31611130036). The research of N.Y. was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute and an endowed professorship from Bayer Healthcare.

ABBREVIATIONS

ATRST1, atrial standstill 1; BRGDA1, Brugada syndrome 1; Cav, voltage-gated calcium; CNS, central nervous system; cryo-EM, cryo-electron microscopy; DS, Dravet syndrome; FEB, febrile seizure; GEFS+2, generalized epilepsy with febrile seizures plus 2; HOKPP2, periodic paralysis hypokalemic 2; HYPP, periodic paralysis hyperkalemic; IEM, primary erythermalgia; LQT3, long QT syndrome 3; MEPPC, multifocal ectopic Purkinje-related premature contractions; Nav, voltage-gated sodium; NKPP, periodic paralysis normokalemic; PEPD, paroxysmal extreme pain disorder; PFHB1A, progressive familial heart block 1A; PMC, paramyotonia congenita of von Eulenburg; SF, selectivity filter; SFN, small fiber neuropathy; SIDS, sudden infant death syndrome; SSS1, sick sinus syndrome 1; VF1, familial paroxysmal ventricular fibrillation 1; VSDs, voltage-sensing domains

COMPLIANCE WITH ETHICS GUIDELINES

Weiyun Huang, Minhao Liu, S. Frank Yan, and Nieng Yan declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

13238_2017_372_MOESM1_ESM.pbd (2.2 mb)
Supplementary material 1 (PDB 2287 kb)

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Authors and Affiliations

  1. 1.State Key Laboratory of Membrane Biology, School of Life Sciences and School of MedicineTsinghua UniversityBeijingChina
  2. 2.Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of MedicineTsinghua UniversityBeijingChina
  3. 3.Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of MedicineTsinghua UniversityBeijingChina
  4. 4.Molecular Design and Chemical Biology, Roche Pharma Research and Early DevelopmentRoche Innovation Center ShanghaiShanghaiChina

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