Pathogenicity of de novo CACNA1D Ca2+ channel variants predicted from sequence co-variation Article Swipe
Xuechen Tang
,
Nadine J. Ortner
,
Yuliia V. Nikonishyna
,
Monica L. Fernández‐Quintero
,
Janik Kokot
,
Jörg Striessnig
,
Klaus R. Liedl
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41431-024-01594-y
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41431-024-01594-y
Voltage-gated L-type Cav1.3 Ca 2+ channels support numerous physiological functions including neuronal excitability, sinoatrial node pacemaking, hearing, and hormone secretion. De novo missense mutations in the gene of their pore-forming α1-subunit ( CACNA1D ) induce severe gating defects which lead to autism spectrum disorder and a more severe neurological disorder with and without endocrine symptoms. The number of CACNA1D variants reported is constantly rising, but their pathogenic potential often remains unclear, which complicates clinical decision-making. Since functional tests are time-consuming and not always available, bioinformatic tools further improving pathogenicity potential prediction of novel variants are needed. Here we employed evolutionary analysis considering sequences of the Cav1.3 α1-subunit throughout the animal kingdom to predict the pathogenicity of human disease-associated CACNA1D missense variants. Co-variation analyses of evolutionary information revealed residue–residue couplings and allowed to generate a score, which correctly predicted previously identified pathogenic variants, supported pathogenicity in variants previously classified as likely pathogenic and even led to the re-classification or re-examination of 18 out of 80 variants previously assessed with clinical and electrophysiological data. Based on the prediction score, we electrophysiologically tested one variant (V584I) and found significant gating changes associated with pathogenic risks. Thus, our co-variation model represents a valuable addition to complement the assessment of the pathogenicity of CACNA1D variants completely independent of clinical diagnoses, electrophysiology, structural or biophysical considerations, and solely based on evolutionary analyses.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41431-024-01594-y
- https://www.nature.com/articles/s41431-024-01594-y.pdf
- OA Status
- hybrid
- Cited By
- 3
- References
- 58
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4393313304
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4393313304Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41431-024-01594-yDigital Object Identifier
- Title
-
Pathogenicity of de novo CACNA1D Ca2+ channel variants predicted from sequence co-variationWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-03-29Full publication date if available
- Authors
-
Xuechen Tang, Nadine J. Ortner, Yuliia V. Nikonishyna, Monica L. Fernández‐Quintero, Janik Kokot, Jörg Striessnig, Klaus R. LiedlList of authors in order
- Landing page
-
https://doi.org/10.1038/s41431-024-01594-yPublisher landing page
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-
https://www.nature.com/articles/s41431-024-01594-y.pdfDirect link to full text PDF
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YesWhether a free full text is available
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-
hybridOpen access status per OpenAlex
- OA URL
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https://www.nature.com/articles/s41431-024-01594-y.pdfDirect OA link when available
- Concepts
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Biology, Missense mutation, Genetics, Pathogenicity, Gene, Phenotype, MicrobiologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
3Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2, 2024: 1Per-year citation counts (last 5 years)
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58Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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