Skip to main content

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

A Correction to this article was published on 12 February 2018

This article has been updated

Abstract

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment—auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Change history

  • 12 February 2018

    The following information was inadvertently omitted in the original publication.

References

  • Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21:1133–1145

    CAS  Article  PubMed  Google Scholar 

  • Bench J, Kowal A, Bamford J (1979) The BKB (Bamford–Kowal–Bench) sentence lists for partially-hearing children. Br J Audiol 13(3):108–112

    CAS  Article  PubMed  Google Scholar 

  • Boothroyd A (1968) Developments in speech audiometry. Br J Audiol (Sound) 2:3–10

    Article  Google Scholar 

  • Brand T, Wagener KC (2017) Characteristics, advantages, and limits of matrix tests (article in German). HNO 65(3):182–188

    CAS  Article  PubMed  Google Scholar 

  • Chilla R, Gabriel P, Kozielski P, Bänsch D, Kabus M (1976) Der Göttinger Speech Kindersprachverständnistest I. HNO 24:342–346

    CAS  PubMed  Google Scholar 

  • Clausen MV, Hilbers F, Poulsen H (2017) The structure and function of the Na, K-ATPase isoforms in health and disease. Front Physiol 8:371

    Article  PubMed  PubMed Central  Google Scholar 

  • Dard R, Mignot C, Durr A, Lesca G, Sanlaville D, Roze E, Mochel F (2015) Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation. Dev Med Child Neurol 57:1183–1186

    Article  PubMed  Google Scholar 

  • Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJM, Friedman JM, FORGE Canada Consortium (2014) A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 9:15

    Article  PubMed  PubMed Central  Google Scholar 

  • Elberling C, Ludvigsen C, Lyregaard PE (1989) DANTALE: a new Danish speech material. Scand Audiol 18:169–175

    CAS  Article  PubMed  Google Scholar 

  • Erichsen S, Zuo J, Curtis L, Rarey K, Hultcrantz M (1996) Na, K-ATPase alpha- and beta-isoforms in the developing cochlea of the mouse. Hear Res 100:143–149

    CAS  Article  PubMed  Google Scholar 

  • Geering K (2005) Function of FXYD proteins, regulators of Na, K-ATPase. J Bioenerg Biomembr 37:387–392

    CAS  Article  PubMed  Google Scholar 

  • Giraudet F, Avan P (2012) Auditory neuropathies: understanding their pathogenesis to illuminate intervention strategies. Curr Opin Neurol 25:50–56

    Article  PubMed  Google Scholar 

  • Han M, Kopec W, Solov’yov IA, Khandelia H (2017) Glutamate water gates in the ion binding pocket of Na+ bound Na+, K+-ATPase. Sci Rep 7:39829

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Harrison RV, Gordon KA, Papsin BC, Negandhi J, James AL (2015) Auditory neuropathy spectrum disorder (ANSD) and cochlear implantation. Int J Pediatr Otolaryngol 79:1980–1987

    Article  Google Scholar 

  • Heimer G, Sadaka Y, Israelian L, Feiglin A, Ruggieri A, Marshall CR, Scherer SW, Ganelin-Cohen E, Marek-Yagel D, TzadokM Nissenkorn A, Anikster Y, Minassian BA, Zeev BB (2015) CAOS-episodic cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss: a third allelic disorder of the ATP1A3 gene. J Child Neurol 30:1749–1756

    Article  PubMed  Google Scholar 

  • Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Jóhannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B, ATP1A3 Working Group (2014) Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 13(5):503–514

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hilbers F, Kopec W, Isaksen TJ, Holm TH, Lykke-Hartmann K, Nissen P, Khandelia H, Poulsen H (2016) Tuning of the Na, K-ATPase by the beta subunit. Sci Rep 6:20442

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Holmgren M, Wagg J, Bezanilla F, Rakowski RF, De Weer P, Gadsby DC (2000) Three distinct and sequential steps in the release of sodium ions by the Na+/K+-ATPase. Nature 403:898–901

    CAS  Article  PubMed  Google Scholar 

  • Jespersen T, Grunnet M, Angelo K, Klaerke DA, Olesen SP (2002) Dual-function vector for protein expression in both mammalian cells and Xenopus laevis oocytes. BioTechniques 32:536–538, and 540

  • Kampfhaus RW (ed) (2005) Clinical assessment of child and adolescent intelligence, 2nd edn. Springer, New York (ISBN-10:0–387-26299-7 and ISBN-13:978–0387262994)

    Google Scholar 

  • Kemp DT (1978) Stimulated acoustic emissions from within the human auditory system. J Acoust Am 64:1386–1391

    CAS  Article  Google Scholar 

  • Kopec W, Loubet B, Poulsen H, Khandelia H (2014) Molecular mechanism of Na(+), K(+)-ATPase malfunction in mutations characteristic of adrenal hypertension. Biochemistry 53:746–754

    CAS  Article  PubMed  Google Scholar 

  • Li C, Geering K, Horisberger J-D (2006) The third sodium binding site of Na, K-ATPase is functionally linked to acidic pH-activated inward current. J Membr Biol 213:1–9

    Article  PubMed  Google Scholar 

  • Maas RP, Schieving JH, Schouten M, Kamsteeg EJ, van de Warrenburg BP (2016) The genetic homogeneity of CAPOS syndrome: four new patients with the c.2452G>A (p.Glu818Lys) mutation in the ATP1A3 gene. Pediatr Neurol 59(71–75):e71

    Article  Google Scholar 

  • Mazzoli M, van Camp G, Nnewton V, Giarbini N, Declau F, Parving A (2003) Recommendations for the description of genetic and audiological data for families with nonsyndromic hereditary hearing impairment. Audiol Med 1:148–150

    Article  Google Scholar 

  • McGuirt JP, Schulte BA (1994) Distribution of immunoreactive alpha- and beta-subunit isoforms of Na, K-ATPase in the gerbil inner ear. J Histochem Cytochem 42:843–853

    CAS  Article  PubMed  Google Scholar 

  • McLean WJ, Smith KA, Glowatzki E, Pyott SJ (2009) Distribution of the Na, K-ATPase alpha subunit in the rat spiral ganglion and organ of corti. J Assoc Res Otolaryngol 10:37–49

    Article  PubMed  Google Scholar 

  • Morth JP, Pedersen BP, Toustrup-Jensen MS, Sørensen TL-M, Petersen J, Andersen JP, Vilsen B, Nissen P (2017) Crystal structure of the sodium-potassium pump. Nature 450. https://doi.org/10.1038/nature06419

  • Moser T, Starr A (2016) Auditory neuropathy—neural and synaptic mechanisms. Nat Rev Neurol 12:135–149

    CAS  Article  PubMed  Google Scholar 

  • Nicolaides P, Appleton RE, Fryer A (1996) Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome. J Med Genet 33:419–421

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Odom JV, Bach M, Brigell M, Hoder GE, McCulloch DL, Tormene AP, Vaegan (2010) ISCEV standard for clinical visual evoked potentials (2009 update). Doc Ophthalmol 120:111–119

    Article  PubMed  Google Scholar 

  • Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Mizota A, Tormene AP (2016) ISCEV standard for clinical visual evoked potentials: (2016 update). Doc Ophthalmol 133:1–9

    Article  PubMed  Google Scholar 

  • Panagiotakaki E, Grandis ED, Stagnaro M, Heinzenb EL, Fons C, Sisodiya S, de Vries B, Goubau C, Weckhuysen S, Kemlink D, Scheffer I, Lesca G, Rabilloud M, Klich A, Ramirez-Camacho A, Ulate-Campos A, Campistol J, Gianotta M, Moutard M-L, Doummar D, Hubsch-Bonneaud C, Jaffer F, Cross H, Gurrieri F, Tiziano D, Nevsimalova S, Neville B, van den Maagdenberg AMJM, Mikati M, Goldstein DB, Vavassori R, Arzimanoglou A, The Italian IBAHC Consortium, The French AHC consortium and the International AHC Consortium (2015) Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood—a study of 155 patients. Orphanet J Rare Dis 10:123

    Article  PubMed  PubMed Central  Google Scholar 

  • Potic A, Nmezi B, Padiath QS (2015) CAPOS syndrome and hemiplegic migraine in a novel pedigree with the specific ATP1A3 mutation. J Neurol Sci 358:453–456

    CAS  Article  PubMed  Google Scholar 

  • Poulsen H, Khandelia H, Morth JP, Bublitz M, Mouritsen OG, Egebjerg J, Nissen P (2010) Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. Nature 467:99–102

    CAS  Article  PubMed  Google Scholar 

  • Price EM, Lingrel JB (1988) Structure-function relationships in the Na, K-ATPase alpha subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine-122 to aspartic acid generates a ouabain-resistant enzyme. Biochemistry 27:8400–8408

    CAS  Article  PubMed  Google Scholar 

  • Rance G, Starr A (2015) Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy. Brain J Neurol 138:3141–3158

    Article  Google Scholar 

  • Rodriguez-Ballesteros M, del Castillo F, Martin Y, Moreno-Pelayo MA, Morera C, Prieto F, Marco J, Morant A, Gallo-Teran J, Morales-Angulo C, Navas C, Trinidad G, Cruz Tapia M, Moreno F, del Castillo I (2003) Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF). Hum Mutat 22:451–456

    CAS  Article  PubMed  Google Scholar 

  • Rosewich H, Weise D, Ohlenbusch A, Gartner J, Brockmann K (2014) Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome. Neurology 83:861–863

    Article  PubMed  Google Scholar 

  • Rouillon I, Marcolla A, Roux I, Marlin S, Feldmann D, Couderc R, Jonard L, Petit C, Denoyelle F, Garabédian EN, Loundon N (2006) Results of cochlear implantation in two children with mutations in the OTOF gene. Int J Pediatr Otorhinolaryngol 70(4):689–696

    CAS  Article  PubMed  Google Scholar 

  • Santarelli R, Rossi R, Scimemi P, Cama E, Valentino ML, La Morgia C, Caporali L, Liguori R, Magnavita V, Monteleone A, Biscaro A, Arslan E, Carelli V (2015) OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain 138:563–576

    Article  PubMed  PubMed Central  Google Scholar 

  • Schuth O, McLean WJ, Eatock RA, Pyott SJ (2014) Distribution of Na, K-ATPase α subunits in rat vestibular sensory epithelia. J Assoc Res Otolaryngol 15:739–754

    Article  PubMed  PubMed Central  Google Scholar 

  • Shinoda T, Ogawa H, Cornelius F, Toyoshima C (2009) Crystal structure of the sodium–potassium pump at 2.4 A resolution. Nature 459:446–450

    CAS  Article  PubMed  Google Scholar 

  • Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI (1996) Auditory neuropathy. Brain 119(Pt 3):741–753

    Article  PubMed  Google Scholar 

  • Starr A, Siniger YS, Winter M, Derebery MJ, Oba S, Michalewski HJ (1998) Transient deafness due to temperature-sensitive auditory neuropathy. Ear Hear 19(3):169–179

    CAS  Article  PubMed  Google Scholar 

  • Sweney MT, Newcomb TM, Swoboda KJ (2015) The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-Parkinsonism, CAPOS and beyond. Pediatr Neurol 52:56–64

    Article  PubMed  Google Scholar 

  • Vedovato N, Gadsby DC (2010) The two C-terminal tyrosines stabilize occluded Na/K pump conformations containing Na or K ions. J Gen Physiol 136:63–82

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Viollet L, Glusman G, Murphy KJ, Newcomb TM, Reyna SP, Sweney M, Nelson B, Andermann F, Andermann E, Acsadi G, Barbano RL, Brown C, Brunkow ME, Chugani HT, Cheyette SR, Collins A, DeBrosse SD, Galas D, Friedman J, Hood L, Huff C, Jorde LB, King MD, LaSalle B, Leventer RJ, Leweit AJ, Massart MB, Mérida MR II, Ptáček LJ, Roach JC, Rust RS, Renault F, Sanger TD, de Menezes MAS, Tennyson R, Uldall P, Zhang Y, Zupanc M, Xin W, Silver K, Swoboda KJ (2015) Alternating hemiplegia of childhood: retrospective genetic study and genotype–phenotype correlations in 187 subjects from the US AHCF Registry. PLoS One 10(5):e0127045. https://doi.org/10.1371/journal.pone.0127045 [Erratum in PLoS One 2015;10(8):e0137370]

    Article  PubMed  PubMed Central  Google Scholar 

  • Watts AG, Sanchez-Watts G, Emanuel JR, Levenson R (1991) Cell-specific expression of mRNAs encoding Na+, K+-ATPase α- and β-subunit isoforms within the rat central nervous system. Proc Natl Acad Sci USA 88:7425–7429

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Weigand KM, Messchaert M, Swarts HG, Russel FG, Koenderink JB (2014) Alternating Hemiplegia of Childhood mutations have a differential effect on Na(+), K(+)-ATPase activity and ouabain binding. Biochim Biophys Acta 1842:1010–1016

    CAS  Article  PubMed  Google Scholar 

  • Yaragatupalli S, Olivera JF, Gatto C, Artigas P (2009) Altered Na+ transport after an intracellular-α-subunit deletion reveals strict external sequential release of Na+ from the Na/K pump. Proc Natl Acad Sci USA 106(36):15507–15512

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Yu H, Ratheal IM, Artigas P, Roux B (2011) Protonation of key acidic residues is critical for the K(+)-selectivity of the Na/K pump. Nat Struct Mol Biol 18:1159–1163

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Lan L, Shi W, Yu L, Xie L, Xiong F, Zhao C, Li N, Yin Z, Zong L, Guan J, Wang D, Sun W, Wang Q (2016) Temperature sensitive auditory neuropathy. Hear Res 335:53–63

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all of the families for their participation. Thanks to Dr. Deirdre Lucas and Dr. Rudrapathy Palaniappan for clinical expertise and data collection in one of the British cases, to Clara van Karnebeek for genetic testing of cases 15 and 16, to Dr. Anne Läßig for phoniatrics in case 18, and to the Swedish expert team of deafblindness. Lone Sandbjerg Hindbæk, Kennedy Center, is thanked for excellent technical help. We thank Hans Ulrik Møller, Department of Ophthalmology, Viborg Hospital for long standing continuous efforts to make a diagnosis in the Danish families, and raising suspicion about mitochondrial aetiology during these efforts. We thank Dr. Marcus Dittrich and Dr. Tobias Müller Müller from the Department of Bioinformatics, the University of Würzburg, Germany, for pipeline development and bioinformatics support in case 18. We would like to thank Arnold Starr, MD, Professor Emeritus Recalled, Neurology and Neurobiology, University California Irvine for critical reading and valuable comments to the manuscript.

Funding

All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. TM is supported by the German Research Foundation through the Leibniz Program.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Lisbeth Tranebjærg or Maria Bitner-Glindzicz.

Ethics declarations

Ethical approval

This is a retrospective study performed in accordance with Helsinki declaration. All patients have given informed consent to publish. For case 18, the study has been approved by the Ethics Committee of the University of Würzburg (approval number: 46/15).

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Christian Hamel died during the processing of the manuscript.

A correction to this article is available online at https://doi.org/10.1007/s00439-018-1870-7.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1.

Representative sequence chromatograms for the ATP1A3 missense mutation c.2452G > A; p.Glu818Lys compared to a normal control. The arrow indicates the nucleotide change of the heterozygous missense mutation. Nomenclature of mutation refers to the ATP1A3 RefSeq NM_152296.4, (Gene ID: NG_008015.1) with nucleotide number +1 being A of the start codon ATG. (PDF 301 kb)

Fig. S2.

A, Preserved OAEs at age 13 in case 3, with noticeable high amplitudes. B, ABR (calibrated in dB peSPL) from left and right ear in case 3 without reproducible responses (PDF 346 kb)

Fig. S3.

Case 12 at age 19 years. A Air conduction thresholds for right (red symbols) and left (blue symbols) ear. B. ABR with click stimulus in rarefaction and condensation mode, right and left ear. Phase-reversed cochlear microphonics at 80 dB nHL and higher intensities in combination with no stimulus artefact. C. Transtympanic electrocochleography with alternating click (right ear). A large summation potential is seen with threshold at 50 dB nHL pointing to preserved inner hair cell function. (PDF 634 kb)

Fig. S4.

Case 14 A, Pure tone audiograms at age 29 years (pale lines) and at 32 years (dark lines) showing some progression in the right ear (red) and possibly in the left ear (blue). B, TEOAE and DPOAE are present in both ears. TEOAE Stimulus 83.7 and 85.8 dBpe, reject level = 48.0dBspl; DPOAE Stimulus = 70/70 dB; 8 pts/octave; F2/F1 – 1.22; reject level = 49.5 dBspl, Otodyamics Ltd ILOv6 C, Click ABR shows no repeatable response at 100 dB nHL in either ear. (PDF 2640 kb)

Fig. S5.

Case 15 A, Pure tone audiogram at age 11 years showing moderate hearing loss. B, TEOAE and DPOAE are present. TEOAE Stimulus 85.8 and 86.9 dBpe, reject level = 49.5 dBspl; DPOAE, Stimulus = 65/55 dB; 3 pts/octave; F2/F1 – 1.22; reject level = 49.5 dBspl, Otodyamics Ltd ILOv6 C, Tone pip ABR shows no repeatable response at 80dBnHL at 4 kHz. D, Click ABR showing cochlear microphonics are present in both ears, more marked on the right. Note that primary low frequencies are affected. (PDF 2889 kb)

Fig. S6.

Case 16 A, Pure tone audiograms at age 8 years (pale lines) and 9 years (dark lines) showing severe low- and high-frequency hearing impairment on the right and profound low and moderate hearing loss on the left ear. There has been progression at 500 Hz in the left ear. B, TEOAE and DPOAE are present in both ears at age 7 years. TEOAE Stimulus 83.7 and 83.7 dBpe, reject level = 54.0 and 50.9 dBspl; DPOAE Stimulus = 65/55 dB; 3 pts/octave; F2/F1 – 1.22; reject level = 49.5 dBspl, Otodyamics Ltd ILOv6 C, Click ABR shows no repeatable response at 90 dB nHL in either ear. D, Click ABR shows cochlear microphonics are present in both ears. (PDF 1094 kb)

Fig. S7.

Optical Coherence Tomography (OCT) measuring the retinal nerve fibre thickness profile (RNFL) from case13. A) Retinal nerve fibre (RNFL) thickness profile (black curve) in case 13 at age 13 years shows a reduced RNFL thickness in all quadrants, temporal (TMP), superior (SUP), inferior (INF) and nasal (NAS) sides, in both eyes. OD, right eye; OS, left eye. The green area defines the 5th to 95th (normal thickness), the yellow area the 1st to 5th (border-line thickness) and the red area below the first percentiles (abnormal thickness). Colour scale of the thickness profile is indicated in the colour bar at the bottom of the figure. On the right, RNFL thickness in individual sectors and clock hours demonstrates decreased RNFL thickness in the superior (S), inferior (I), nasal (N) and temporal (T) quadrants of right and left eyes. RNFL measurements in corresponding quadrants are noted in μm. The table represents key parameters of optic nerve head and RNFL analysis. There is severe decreased average RNFL thickness with an average RNFL thickness of 45.22 μm in the right eye and 47.22 μm in the left eye. B) Eye fundus picture of affected case13 shows pale, almost white optic nerve of the left eye at age 26 years. In unaffected people the optic nerve appears pink. (PDF 239 kb)

Supplementary material 8 (PDF 151 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tranebjærg, L., Strenzke, N., Lindholm, S. et al. The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management. Hum Genet 137, 111–127 (2018). https://doi.org/10.1007/s00439-017-1862-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-017-1862-z