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. Ca(v)1.3 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 Ca(v)1.3 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.

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

“…The only significant change was a small reduction in maximal current amplitude compared to WT in both splice variants. However, based on findings in Ca v 1.3 knockout mice and humans with CACNA1D mutations [19,20], a loss-of-function phenotype by a heterozygous de novo mutation is unlikely to be pathogenic. At present, we cannot rule out the possibility that a special combination of accessory β- and α2δ-subunits, other splice variants or a yet unknown molecular mechanism not active in our expression system can unmask functional changes in M1354I channels.…”

“…Based on findings in Ca v 1.3-deficient mice [19] and humans [20] heterozygous de novo loss-of-function mutations are expected to be clinically silent and only missense mutations with gating changes permitting enhanced Ca 2+ signaling are likely to be disease relevant. However, the functional consequences of such mutations are difficult to predict in silico .…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…A homozygous 3-bp insertion in CACNA1D , inducing p.G403_404ins, was first screened from a Pakistani family with pronounced bradycardia. This p.G403_404ins, located at alternative spliced exon 8b of Ca V α 1D , resulted in nonconducting Ca V 1.3 channels [126], which may explain the phenotype of bradycardia.…”

“…For example, alternative splicing, one of most important mechanisms of post-transcriptional modification [130,131], generates more than 20 alternative spliced exons in α 1C mRNA, which forms many variants of α 1C [14,60,132]. It has been indicated the mutations in these alternative spliced exons of LTCC can also attribute to the abnormal cardiac excitation [61,62,126]. Therefore, it is noteworthy to screen the potential mutations in these alternative spliced exons of LTCC in the patients with cardiac arrhythmias.…”

L-type calcium channels in the auditory system

“…A total of ten different genes encode the α 1 Mice with ablation of Cacna1d, the gene that encodes Ca v 1.3, are deaf [24], and humans with a mutation in Ca v 1.3, which inhibits channel opening, suffer from congenital deafness [1]. Both the Cacna1d −/− mice and humans with Cacna1d mutations exhibit accompanying bradycardia, which indicates Ca v 1.3 participation in sinoatrial nodal rhythm generation.…”