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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\u2013endosome 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.<\/jats:p>","DOI":"10.1242\/dmm.050546","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T10:03:44Z","timestamp":1709546624000},"source":"Crossref","is-referenced-by-count":7,"title":["Functional and <i>in silico<\/i> analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases"],"prefix":"10.1242","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8247-6289","authenticated-orcid":false,"given":"Eli","family":"Matsell","sequence":"first","affiliation":[{"name":"University of British Columbia 1 Department of Biochemistry & Molecular Biology , , Vancouver, British Columbia V6T 1Z3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0654-4300","authenticated-orcid":false,"given":"Jens Peter","family":"Andersen","sequence":"additional","affiliation":[{"name":"Aarhus University 2 Department of Biomedicine , , 8000 Aarhus , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4479-1831","authenticated-orcid":false,"given":"Robert S.","family":"Molday","sequence":"additional","affiliation":[{"name":"University of British Columbia 1 Department of Biochemistry & Molecular Biology , , Vancouver, British Columbia V6T 1Z3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"key":"2024050112203796100_DMM050546C1","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1146\/annurev.bi.36.070167.003455","article-title":"Biochemical aspects of active transport","volume":"36","author":"Albers","year":"1967","journal-title":"Annu. 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