Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.
| Title: | Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. |
|---|---|
| Authors: | Xi Luo, Jill A Rosenfeld, Shinya Yamamoto, Tamar Harel, Zhongyuan Zuo, Melissa Hall, Klaas J Wierenga, Matthew T Pastore, Dennis Bartholomew, Mauricio R Delgado, Joshua Rotenberg, Richard Alan Lewis, Lisa Emrick, Carlos A Bacino, Mohammad K Eldomery, Zeynep Coban Akdemir, Fan Xia, Yaping Yang, Seema R Lalani, Timothy Lotze, James R Lupski, Brendan Lee, Hugo J Bellen, Michael F Wangler, Members of the UDN |
| Source: | PLoS Genetics, Vol 13, Iss 7, p e1006905 (2017) |
| Publisher Information: | Public Library of Science (PLoS), 2017. |
| Publication Year: | 2017 |
| Collection: | LCC:Genetics |
| Subject Terms: | Genetics, QH426-470 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1553-7390 1553-7404 |
| Relation: | http://europepmc.org/articles/PMC5557584?pdf=render; https://doaj.org/toc/1553-7390; https://doaj.org/toc/1553-7404 |
| DOI: | 10.1371/journal.pgen.1006905 |
| Access URL: | https://doaj.org/article/56bd9b19ccf04563bd8e2253cc607059 |
| Accession Number: | edsdoj.56bd9b19ccf04563bd8e2253cc607059 |
| Database: | Directory of Open Access Journals |
| ISSN: | 15537390 15537404 |
|---|---|
| DOI: | 10.1371/journal.pgen.1006905 |
| Published in: | PLoS Genetics |
| Language: | English |