Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026850 (
muscular dystrophy
)
5,870
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Transmembrane protein 16E (TMEM16E) belongs to the TMEM16 family of proteins that have 10 transmembrane regions and appears to localize intracellularly. Although TMEM16E mutations cause bone fragility and
muscular dystrophy
in humans, its biochemical function is unknown. In the TMEM16 family, TMEM16A and -16B serve as Ca(2+)-dependent Cl(-) channels, while TMEM16C, -16D, -16F, -16G, and -16J support Ca(2+)-dependent phospholipid scrambling. Here, we show that TMEM16E carries a segment composed of 35 amino acids homologous to the scrambling domain in TMEM16F. When the corresponding segment of TMEM16A was replaced by this 35-amino-acid segment of TMEM16E, the chimeric molecule localized to the plasma membrane and supported Ca(2+)-dependent scrambling. We next established TMEM16E-deficient mice, which appeared to have normal skeletal muscle. However, fertility was decreased in the males. We found that TMEM16E was expressed in germ cells in early spermatogenesis and thereafter and localized to sperm tail. TMEM16E(-/-) sperm showed no apparent defect in morphology, beating, mitochondrial function, capacitation, or binding to zona pellucida. However, they showed reduced motility and inefficient fertilization of cumulus-free but zona-intact eggs in vitro. Our results suggest that TMEM16E may function as a
phospholipid scramblase
at inner membranes and that its defect affects sperm motility.
...
PMID:A Role of TMEM16E Carrying a Scrambling Domain in Sperm Motility. 2666 38
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 Ca
2+
-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.
...
PMID:TMEM16E/ANO5 mutations related to bone dysplasia or muscular dystrophy cause opposite effects on lipid scrambling. 3211 55
