A neurodevelopmental disorder caused by a dysfunctional CACNA1A allele
Audra A Kramer1, Daniel F Bennett1, Kristin W Barañano2
1Department of Pathology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD 21201, USA.
Eneurologicalsci
|March 20, 2023
Summary
A CACNA1A gene mutation caused a severe neurological disorder by preventing calcium channel formation. This study suggests the condition results from haploinsufficiency, where one copy of the gene is insufficient.
Area of Science:
- Neuroscience
- Genetics
- Channelopathies
Background:
- P/Q-type Ca2+ flux via CaV2.1 channels is crucial for neurotransmission.
- Mutations in the CACNA1A gene, encoding CaV2.1, lead to pediatric neurological disorders.
Purpose of the Study:
- To investigate the functional consequences of a novel de novo CACNA1A frameshift mutation.
- To determine the underlying mechanism of a patient's neurological symptoms.
Main Methods:
- Identified a patient with a de novo CACNA1A frameshift mutation (c.5018dupG).
- Performed patch-clamp electrophysiology on tsA-201 cells expressing the mutant CaV2.1 channel (p.Gln1674Serfs*43).
Main Results:
- The CACNA1A mutation resulted in a truncated CaV2.1 protein (p.Gln1674Serfs*43).
- Electrophysiology showed a complete absence of Ba2+ current in cells expressing the mutant channel.
- The mutant channel's inability to form a functional pore led to ablated divalent flux.
Conclusions:
- The identified frameshift mutation in CACNA1A leads to a loss-of-function by preventing channel pore formation.
- The patient's neurological symptoms are likely caused by effective haploinsufficiency of the CACNA1A gene.
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