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


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.

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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.

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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




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.

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The authors declare no competing financial interests.

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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).

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