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PLoS Genet. 2017 Jul 24;13(7):e1006905. doi: 10.1371/journal.pgen.1006905. eCollection 2017 Jul.

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America.
2
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United States of America.
3
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America.
4
University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
5
Nationwide Children's Hospital & The Ohio State University, Columbus, OH, United States of America.
6
Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center andTexas Scottish Rite Hospital, Dallas, TX, United States of America.
7
Houston Specialty Clinic, Houston, TX, United States of America.
8
Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States of America.
9
Texas Children's Hospital, Houston, TX, United States of America.
10
Howard Hughes Medical Institute, Houston TX, United States of America.

Abstract

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.

PMID:
28742085
PMCID:
PMC5557584
DOI:
10.1371/journal.pgen.1006905
[Indexed for MEDLINE]
Free PMC Article

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