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Cis-Regulatory Enhancer Mutations are a Cause of Human Limb Malformations

  • Julia E. VanderMeer
  • Nadav AhituvEmail author
Chapter

Abstract

Congenital limb malformations are the second most common class of human birth defects and can be caused both by environmental and genetic factors. While it is known that some limb malformations are the result of coding mutations that disrupt genes, identifying the causal mutation in a patient with an isolated limb malformation is often difficult. This may be due in part to the growing number of cases with isolated limb malformations that are shown to be the result of nucleotide changes in gene regulatory elements. These regulatory mutations affect gene expression in the developing limb and can cause dramatic changes to patterning, leading to congenital limb malformations. In this chapter, we will review characterized gene regulatory mutations leading to human limb malformations and also provide evidence that additional limb enhancers could be the cause of other human limb malformations.

Keywords

Limb Sonic hedgehog ZPA ZRS BMP2 SOX9 Polydactyly Brachydactyly 

Abbreviations

AER

Apical ectodermal ridge

AP

Anterior-posterior [axis]

BDA2

Brachydactyly type A2

BMP

Bone morphogenic protein

BMP2

Bone morphogenic protein 2

bp

Base pairs

ChIP

Chromatin immunoprecipitation

ChIP-seq

Chromatin immunoprecipitation followed by deep sequencing

DLX5/6

Distal-less homeobox 5 and 6

DV

Dorsal-ventral [axis]

FGF4

Fibroblast growth factor 4

FGF8

Fibroblast growth factor 8

FGF10

Fibroblast growth factor 10

GLI3

GLI family zinc finger 3

GREM1

Gremlin 1

HOX

Homeobox

kb

Kilobase

LMBR1

Limb region 1

PD

Proximal-distal [axis]

PITX1

Paired-like homeodomain 1

PPD

Preaxial polydactyly

PTHLH

Parathyroid hormone-like hormone

SHFM

Split hand-foot malformation

SHH

Sonic hedgehog

SOX9

SRY-box containing gene 9

TBX4

T-box 4

TF

Transcription factor

TPT

Triphalangeal thumb

TPTPS

Triphalangeal thumb polysyndactyly

ZPA

Zone of polarizing activity

ZRS

ZPA regulatory sequence

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Bioengineering and Therapeutic Sciences, Institute for Human GeneticsUniversity of California San FranciscoSan FranciscoUSA

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