ArticleDisease models & mechanisms2024
Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.
Article in Disease models & mechanisms, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 6 citations in OpenAlex.
- Loss of Atp8a2 drives neurodegeneration through the dysregulation of spatiotemporal phosphatidylserine externalization in mature neurons.Cell death & disease · 2026Article
- Gene-Diet Interaction Analysis in UK Biobank Identified Genetic Loci That Modify the Association Between Fish Oil Supplementation and the Incidence of Dementia.Current developments in nutrition · 2025Article
- A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes.Neurogenetics · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
- Translating multiscale research in rare disease.Disease models & mechanisms · 2024Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.
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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.