Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Alleles* ; Genome, Human*; Calcium Channels/*genetics ; Cerebellar Ataxia/*genetics ; Neurodegenerative Diseases/*genetics; Animals ; Animals, Genetically Modified ; Cerebellar Ataxia/diagnostic imaging ; Child ; Child, Preschool ; Drosophila melanogaster/genetics ; Female ; Genome-Wide Association Study ; Humans ; Male ; Microscopy, Electron, Transmission ; Mutation, Missense ; Neuroimaging ; Phenotype ; Point Mutation

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

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T32 GM007526 United States GM NIGMS NIH HHS; U54 HD083092 United States HD NICHD NIH HHS; UM1 HG006542 United States HG NHGRI NIH HHS; U01 HG007709 United States HG NHGRI NIH HHS; R01 HG011795 United States HG NHGRI NIH HHS; R01 GM067858 United States GM NIGMS NIH HHS; U01 HG007943 United States HG NHGRI NIH HHS; U54 NS093793 United States NS NINDS NIH HHS; R24 OD022005 United States OD NIH HHS

0 (CACNA1A protein, human)
0 (Calcium Channels)

Date Created: 20170726 Date Completed: 20170821 Latest Revision: 20240207

20240207

PMC5557584

10.1371/journal.pgen.1006905

28742085