Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function
Open accessAbstract
Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.
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Clear evidence from Timothy syndrome shows that improper Ca2+ channel function can cause ASD with penetrance as high as 60-80%.
“Further, there is clear evidence from Timothy syndrome (TS), a rare genetic disorder arising from mutation of either CACNA1C or CACNB2, that improper function of a Ca2+ channel can engender ASD with a penetrance as high as 60-80% (Breitenkamp et al., 2014; Splawski et al., 2005; Splawski et al., 2004).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Breitenkamp et al., 2014
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Calciopathies and Neuropsychiatric Disorders: Physiological and Genetic Aspects
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Calciopathies and Neuropsychic Disorders: Physiological and Genetic Aspects
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- Authors
- Breitenkamp, A. F. S., Matthes, J., Nass, R. D., Sinzig, J., Lehmkuhl, G., Nürnberg, P., & Herzig, S.
- Affiliations
- University of Cologne (DE)
- Corresponding author
- Herzig, Stefan
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-04-21
- Volume
- 9
- Issue
- 4
- Pages
- e95579
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3994086
- OpenAlex
- W1976320686
- Cited by
- 49
- References
- 47
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 10 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 1
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Autism Speaks
- Deutsche Forschungsgemeinschaft
- Universität Ulm
- National Institute of Mental Health (U24MH081810)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- CACNB2, autism spectrum disorder, L-type calcium channels, calcium homeostasis, barium currents, time-dependent inactivation, voltage-dependent inactivation, CACNA1C, Timothy syndrome, genetic susceptibility loci
- MeSH terms
- Amino Acid Sequence, Base Sequence, Child Development Disorders, Pervasive, Family, Humans, Molecular Sequence Data, RNA Splicing, Time Factors, Ion Channel Gating, Point Mutation, Calcium Channels, L-Type, HEK293 Cells
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