Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness

Abstract

Deafness is genetically very heterogeneous and forms part of several syndromes. So far, delayed rectifier potassium channels have been linked to human deafness associated with prolongation of the QT interval on electrocardiograms and ventricular arrhythmia in Jervell and Lange-Nielsen syndrome. Cav1.3 voltage-gated L-type calcium channels (LTCCs) translate sound-induced depolarization into neurotransmitter release in auditory hair cells and control diastolic depolarization in the mouse sinoatrial node (SAN). Human deafness has not previously been linked to defects in LTCCs. We used positional cloning to identify a mutation in CACNA1D, which encodes the pore-forming α1 subunit of Cav1.3 LTCCs, in two consanguineous families with deafness. All deaf subjects showed pronounced SAN dysfunction at rest. The insertion of a glycine residue in a highly conserved, alternatively spliced region near the channel pore resulted in nonconducting calcium channels that had abnormal voltage-dependent gating. We describe a human channelopathy (termed SANDD syndrome, sinoatrial node dysfunction and deafness) with a cardiac and auditory phenotype that closely resembles that of Cacna1d−/− mice.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: SANDD syndrome mutation c.1208_1209insGGG.
Figure 2: Haplotype analysis of families with SANDD syndrome.
Figure 3: Audiograms from people with SANDD syndrome and normal controls.
Figure 4: ECG recordings from people with SANDD syndrome and normal controls.
Figure 5: Cav1.3 α1 subunit containing the p.403_404insGly mutation.
Figure 6: Biophysical properties of wild-type and mutant Cav1.3 LTCCs.
Figure 7: Cav1.3 transcripts containing exon 8A and exon 8B in IHCs and SAN.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Hilgert, N., Smith, R.J. & Van Camp, G. Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics? Mutat. Res. 681, 189–196 (2009).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Cohen, M., Bitner-Glindzicz, M. & Luxon, L. The changing face of Usher syndrome: clinical implications. Int. J. Audiol. 46, 82–93 (2007).

    Article  PubMed  Google Scholar 

  3. 3

    Bitner-Glindzicz, M. & Tranebjaerg, L. The Jervell and Lange-Nielsen syndrome. Adv. Otorhinolaryngol. 56, 45–52 (2000).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Dou, H. et al. Null mutation of alpha1D Ca2+ channel gene results in deafness but no vestibular defect in mice. J. Assoc. Res. Otolaryngol. 5, 215–226 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Platzer, J. et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102, 89–97 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Fukushima, K. et al. An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6. Genome Res. 5, 305–308 (1995).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Woods, C.G. et al. Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am. J. Hum. Genet. 78, 889–896 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Naz, S. et al. Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am. J. Hum. Genet. 71, 632–636 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Sinnegger-Brauns, M.J. et al. Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels. J. Clin. Invest. 113, 1430–1439 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Striessnig, J. & Koschak, A. Exploring the function and pharmacotherapeutic potential of voltage-gated Ca2+ channels with gene knockout models. Channels (Austin) 2, 233–251 (2008).

    Article  Google Scholar 

  11. 11

    Seino, S. et al. Cloning of the alpha 1 subunit of a voltage-dependent calcium channel expressed in pancreatic beta cells. Proc. Natl. Acad. Sci. USA 89, 584–588 (1992).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Striessnig, J., Bolz, H.J. & Koschak, A. Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels. Pflugers Arch. 460, 361–374 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Hoda, J.C., Zaghetto, F., Koschak, A. & Striessnig, J. Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Cav1.4 L-type Ca2+ channels. J. Neurosci. 25, 252–259 (2005).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Splawski, I. et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc. Natl. Acad. Sci. USA 102, 8089–8096, discussion 8086–8088 (2005).

    CAS  Article  Google Scholar 

  15. 15

    McDonough, S.I., Mori, Y. & Bean, B.P. FPL 64176 modification of Cav1.2 L-type calcium channels: dissociation of effects on ionic current and gating current. Biophys. J. 88, 211–223 (2005).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Jones, L.P., Patil, P.G., Snutch, T.P. & Yue, D.T. G-protein modulation of N-type calcium channel gating current in human embryonic kidney cells (HEK 293). J. Physiol. (Lond.) 498, 601–610 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Bangalore, R., Mehrke, G., Gingrich, K., Hofmann, F. & Kass, R.S. Influence of L-type Ca channel alpha 2/delta-subunit on ionic and gating current in transiently transfected HEK 293 cells. Am. J. Physiol. 270, H1521–H1528 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Kamp, T.J., Perez-Garcia, M.T. & Marban, E. Enhancement of ionic current and charge movement by coexpression of calcium channel beta 1A subunit with alpha 1C subunit in a human embryonic kidney cell line. J. Physiol. (Lond.) 492, 89–96 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Koschak, A. et al. Alpha 1D Cav1.3 subunits can form l-type Ca2+ channels activating at negative voltages. J. Biol. Chem. 276, 22100–22106 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Mangoni, M.E. et al. Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc. Natl. Acad. Sci. USA 100, 5543–5548 (2003).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Neyroud, N. et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat. Genet. 15, 186–189 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Splawski, I., Timothy, K.W., Vincent, G.M., Atkinson, D.L. & Keating, M.T. Molecular basis of the long-QT syndrome associated with deafness. N. Engl. J. Med. 336, 1562–1567 (1997).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Tyson, J. et al. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum. Mol. Genet. 6, 2179–2185 (1997).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Busquet, P. et al. CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype. Int. J. Neuropsychopharmacol. 13, 499–513 (2010).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Chan, C.S. et al. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature 447, 1081–1086 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Guzman, J.N., Sanchez-Padilla, J., Chan, C.S. & Surmeier, D.J. Robust pacemaking in substantia nigra dopaminergic neurons. J. Neurosci. 29, 11011–11019 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    McKinney, B.C. & Murphy, G.G. The L-type voltage-gated calcium channel Cav1.3 mediates consolidation, but not extinction, of contextually conditioned fear in mice. Learn. Mem. 13, 584–589 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Singh, A. et al. Modulation of voltage- and Ca2+-dependent gating of Cav1.3 L-type calcium channels by alternative splicing of a C-terminal regulatory domain. J. Biol. Chem. 283, 20733–20744 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Olson, P.A. et al. G protein–coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a Shank-binding domain. J. Neurosci. 25, 1050–1062 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Mangoni, M.E. & Nargeot, J. Genesis and regulation of the heart automaticity. Physiol. Rev. 88, 919–982 (2008).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Lakatta, E.G., Maltsev, V.A. & Vinogradova, T.M. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ. Res. 106, 659–673 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Splawski, I. et al. Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Raybaud, A. et al. The role of the GX9GX3G motif in the gating of high voltage-activated Ca2+ channels. J. Biol. Chem. 281, 39424–39436 (2006).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Long, S.B., Campbell, E.B. & Mackinnon, R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309, 897–903 (2005).

    CAS  Article  Google Scholar 

  35. 35

    Stary, A., Shafrir, Y., Hering, S., Wolschann, P. & Guy, H.R. Structural model of the Cav1.2 pore. Channels (Austin) 2, 210–215 (2008).

    Article  Google Scholar 

  36. 36

    Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. GRR: graphical representation of relationship errors. Bioinformatics 17, 742–743 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    O'Connell, J.R. & Weeks, D.E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63, 259–266 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    CAS  Article  Google Scholar 

  39. 39

    Gudbjartsson, D.F., Jonasson, K., Frigge, M.L. & Kong, A. Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13 (2000).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Rüschendorf, F. & Nurnberg, P. ALOHOMORA: a tool for linkage analysis using 10K SNP array data. Bioinformatics 21, 2123–2125 (2005).

    Article  PubMed  Google Scholar 

  41. 41

    Thiele, H. & Nurnberg, P. HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21, 1730–1732 (2005).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Singh, A. et al. C-terminal modulator controls Ca2+-dependent gating of Cav1.4 L-type Ca2+ channels. Nat. Neurosci. 9, 1108–1116 (2006).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Safayhi, H. et al. L-type calcium channels in insulin-secreting cells: biochemical characterization and phosphorylation in RINm5F cells. Mol. Endocrinol. 11, 619–629 (1997).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Brandt, N. et al. Thyroid hormone deficiency affects postnatal spiking activity and expression of Ca2+ and K+ channels in rodent inner hair cells. J. Neurosci. 27, 3174–3186 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Knirsch, M. et al. Persistence of Cav1.3 Ca2+ channels in mature outer hair cells supports outer hair cell afferent signaling. J. Neurosci. 27, 6442–6451 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Brandt, A., Khimich, D. & Moser, T. Few Cav1.3 channels regulate the exocytosis of a synaptic vesicle at the hair cell ribbon synapse. J. Neurosci. 25, 11577–11585 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the families who have participated in this study, K. Beam and W. Sandtner for discussion on gating currents, M. Thoenes, K. Zimmermann, S. Blick, G. Gajic and S. Kasperek for technical assistance, B. Ali for help with ECG recordings, K. Boss for discussion of the manuscript and C. Striessnig for artwork. This work was supported by the Geers-Stiftung, Bonn; Imhoff-Stiftung, Köln; Köln Fortune, University Hospital of Cologne, Deutsche Forschungsgemeinschaft (BO2954/1‐2); Forschung contra Blindheit: Initiative Usher‐Syndrom e.V. (to H.J.B.); the Austrian Science Fund (P-20670); the Agence Nationale pour la Recherche (ANR-06-PHYSIO-004-01 to M.E.M.); the Fondation de France; the Marie Curie Research Training Network CavNET (MRTN-CT-2006-035367); and the University of Innsbruck (to J.S. and A.K.).

Author information

Affiliations

Authors

Contributions

S.M.B. coordinated and conducted the identification of families with deafness and collection of DNA samples and clinical data. A.A., I.A. and M.F. arranged clinical investigations. H.U.K. facilitated and conducted most of the clinical investigations at Khyber Teaching Hospital, Peshawar. G.N. and P.N. performed genetic mapping. C.D. performed molecular genetic analyses. A.K. and A.L. performed electrophysiological analyses. M.G. cloned wild-type and mutant channels and performed PCR and western blot analysis. M.J.S.-B. performed PCR analysis. N.B., J.E. and M.E.M. provided IHC and SAN tissues. A.K. and J.S. coordinated experiments and wrote the manuscript. H.J.B. initiated, planned and coordinated the study and wrote the manuscript.

Corresponding authors

Correspondence to Jörg Striessnig or Hanno J Bolz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 1198 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Baig, S., Koschak, A., Lieb, A. et al. Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci 14, 77–84 (2011). https://doi.org/10.1038/nn.2694

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing