Journal
HUMAN MUTATION
Volume 41, Issue 6, Pages 1157-1170Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.24006
Keywords
anoctamin; gnathodiaphyseal dysplasia; phosphatidylserine; phospholipid scramblase; TMEM16
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Funding
- Compagnia di San Paolo [2013.0922]
- Fondazione Telethon [GEP15078]
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Mutations in the human TMEM16E/ANO5 gene are causative for gnathodiaphyseal dysplasia (GDD), a rare bone malformation and fragility disorder, and for two types of muscular dystrophy (MD). Previous studies have demonstrated that TMEM16E/ANO5 is a Ca2+-activated phospholipid scramblase and that the mutation c.1538C>T (p.Thr513Ile) causing GDD leads to a gain-of-function phenotype. Here, using established HEK293-based functional assays, we investigated the effects of MD-related and further GDD-related amino acid exchanges on TMEM16E/ANO5 function in the same expression system. These experiments also revealed that the gradual changes in HEK293 cell morphology observed upon expression of TMEM16E/ANO5(GDD) mutants are a consequence of aberrant protein activity. Our results collectively demonstrate that, on the level of protein function, MD mutations are associated to loss-of-function and GDD mutations to gain-of-function phenotypes, confirming conjectures made on the basis of inheritance modes.
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