Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

TitleClinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.
Publication TypeJournal Article
Year of Publication2017
AuthorsLuo, X, Rosenfeld, JA, Yamamoto, S, Harel, T, Zuo, Z, Hall, M, Wierenga, KJ, Pastore, MT, Bartholomew, D, Delgado, MR, Rotenberg, J, Lewis, RAlan, Emrick, L, Bacino, CA, Eldomery, MK, Akdemir, ZCoban, Xia, F, Yang, Y, Lalani, SR, Lotze, T, Lupski, JR, Lee, B, Bellen, HJ, Wangler, MF
Corporate AuthorsMembers of the UDN
JournalPLoS Genet
Date Published2017 Jul
KeywordsAlleles, Animals, Animals, Genetically Modified, Calcium Channels, Cerebellar Ataxia, Child, Child, Preschool, Drosophila melanogaster, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Microscopy, Electron, Transmission, Mutation, Missense, Neurodegenerative Diseases, 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.

Alternate JournalPLoS Genet.
PubMed ID28742085
PubMed Central IDPMC5557584
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States
R01 GM067858 / GM / NIGMS NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States
R24 OD022005 / OD / NIH HHS / United States