Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance

Liaqat, Khurram; Schrauwen, Isabelle; Raza, Syed M.; Lee, Kwanghyuk; Hussain, Shabir; Chakchouk, Imen; Nasır, Abdul; Acharya, Anushree; Abbe, Izoduwa; Umair, Muhammad; Ansar, Muhammad; Ullah, Irfan; Shah, Khadim; Bamshad, Michael J.; Nickerson, Deborah A.; Ahmad, Wasim; Leal, Suzanne M.

doi:10.1038/s10038-018-0542-8

Cited by 36 publications

(31 citation statements)

References 27 publications

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“…It is also in line with previous studies in mice (for a review, see [3]) and humans [24,25]. These found that heterozygous loss-offunction of Cav1.3 is unlikely to cause symptomatic neurodevelopmental disorders and even homozygous loss of Cav1.3 function has not been reported to cause neuropsychiatric behavioral changes [3,24,25,41]. Therefore, a unifying feature of all pathogenic mutations described so far is the potential to induce gating changes that can enhance Cav1.3 function during neuronal activity.…”

Section: Discussionsupporting

confidence: 91%

“…This nicely fits our prediction that only CACNA1D mutations which can also support channel gain-of-function confer high risk for neurodevelopmental disorders. It is also in line with previous studies in mice (for a review, see [3]) and humans [24,25]. These found that heterozygous loss-offunction of Cav1.3 is unlikely to cause symptomatic neurodevelopmental disorders and even homozygous loss of Cav1.3 function has not been reported to cause neuropsychiatric behavioral changes [3,24,25,41].…”

Section: Discussionsupporting

confidence: 90%

“…While our data argue for a high disease risk due to Cav1.3 gain-of-function, heterozygous de novo CACNA1D variants resulting in a loss of Cav1.3 activity are unlikely to cause human disease. This is strongly supported by previous findings both in knockout mice (for a review, see [3]) and Cav1.3-deficient humans with sinoatrial node dysfunction and deafness (SANDD; OMIM #614896 [24,25]), in which functional loss of one or both CACNA1D alleles did not lead to a central nervous system (CNS) disease phenotype. This complicates the classification of new CACNA1D variants as high-risk mutations in genetic studies.…”

Section: Introductionsupporting

confidence: 81%

“…Accordingly, like any of the other previously described pathogenic variants, S652L has not been reported in the genomes of 141,456 control individuals free from pediatric disease (gnomAD database [21];). In contrast, the pathogenic potential should be low or absent from missense mutations causing gating defects favoring reduced function, as outlined above, in mice [40,41] and humans [24,25]. Interestingly, the gnomAD database also reports the rare variant p.Ser672Trp (chr3: 53757881 C>G, human reference genome hg19) variant (S652W), located in the same position as S652L, in three healthy unrelated individuals.…”

Section: Mutation S652w Produces a Loss Of Cav13 Channel Functionmentioning

confidence: 99%

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Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

et al. 2020

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Background: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 Ltype Ca 2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely diseasecausing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods: For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results: Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~13-17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca 2+-levels during action potential-like stimulations, characteristic for gain-offunction changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca 2+-channel blocker isradipine by 3-4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca 2+-channel blockers.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Introductionsupporting

confidence: 81%

Section: Mutation S652w Produces a Loss Of Cav13 Channel Functionmentioning

confidence: 99%

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Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

et al. 2020

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“…As a corollary, our study indicates that functional association of L-type Ca v 1.2 channels and f-channels is not sufficient to maintain normal SAN pacemaking and heart automaticity. Finally, our study provides new mechanistic insight into congenital and autoimmune SAN dysfunction and atrioventricular block based on SAN-VGCC loss-of-function 29,30,49 . Animals were housed in individual cages with free access to food and water and were exposed to 12-h light/dark reverse cycles (light, 20:00 h to 8:00 h) in a thermostatically controlled room.…”

Section: Resultsmentioning

confidence: 87%

Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity

Baudot

Torre

Bidaud

et al. 2020

Sci Rep

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Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2+ channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Cav1.3 (Cav1.3−/−) or Cav3.1 (Cav3.1−/−) channels and double mutant Cav1.3−/−/Cav3.1−/− mice expressing only Cav1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na+ channels. In beating SAN cells, ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based “Ca2+clock” mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart automaticity and define an integral role for these channels in mechanisms that control the heartbeat.

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European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

Arthur

Semsarian

Manlio

et al. 2022

Journal of Arrhythmia

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Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance

Cited by 36 publications

References 27 publications

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

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