TMEM16E/ANO5 mutations related to bone dysplasia or muscular dystrophy cause opposite effects on lipid scrambling.
Hum Mutat
; 41(6): 1157-1170, 2020 06.
Article
en En
| MEDLINE
| ID: mdl-32112655
ABSTRACT
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/ANO5GDD 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteogénesis Imperfecta
/
Anoctaminas
/
Distrofias Musculares
Límite:
Humans
Idioma:
En
Revista:
Hum Mutat
Asunto de la revista:
GENETICA MEDICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Italia