ArticlePLoS genetics2017
Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 89 citations in OpenAlex.
- Calcium channelopathies and intellectual disability: a systematic review.Orphanet journal of rare diseases · 2021Pooled it
- Mitochondrial and lysosomal dysfunctions might be involved in the pathogenesis of the CACNA1A-related neurodevelopmental disorders according to in vitro studies.Biological research · 2025Article
- Wings of Discovery: UsingCells · 2025Review
- Functional analysis of human EED variants using Drosophila.Genetics · 2025Article
- CACNA1A loss-of-function affects neurogenesis in human iPSC-derived neural models.Cellular and molecular life sciences : CMLS · 2025Article
- Intermittent fasting reprograms the brain proteome to prevent synaptic degeneration and cognitive impairment in vascular dementia.Theranostics · 2025Article
- Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.American journal of human genetics · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- Gene Expression at the Tripartite Synapse: Bridging the Gap Between Neurons and Astrocytes.Advances in neurobiology · 2024Review
- Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens.Molecular psychiatry · 2023Article
- Paroxysmal Tonic Upward Gaze: A Clinical Clue for CACNA1A-Related Disorders.Movement disorders clinical practice · 2023Article
- A neurodevelopmental disorder caused by a dysfunctionaleNeurologicalSci · 2023Article
- De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders.American journal of human genetics · 2023Article
- The genotype-phenotype correlations of theFrontiers in molecular neuroscience · 2023Article
- CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options.Handbook of experimental pharmacology · 2023Review
- Review
- DiffBrainNet: Differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions.Neurobiology of stress · 2022Article
- Clinical and genetic characterization of CACNA1A-related disease.Clinical genetics · 2022Article
- The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.Human molecular genetics · 2022Article
Corrections and comments
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Authors and funding
25 authors at 5 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.