We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Gain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia.
- Authors
Di Zanni, Eleonora; Gradogna, Antonella; Scholz-Starke, Joachim; Boccaccio, Anna
- Abstract
Mutations in the human <italic>TMEM16E</italic> (<italic>ANO5</italic>) gene are associated both with the bone disease gnathodiaphyseal dysplasia (GDD; OMIM: 166260) and muscle dystrophies (OMIM: 611307, 613319). However, the physiological function of TMEM16E has remained unclear. We show here that human TMEM16E, when overexpressed in mammalian cell lines, displayed partial plasma membrane localization and gave rise to phospholipid scrambling (PLS) as well as non-selective ionic currents with slow time-dependent activation at highly depolarized membrane potentials. While the activity of wild-type TMEM16E depended on elevated cytosolic Ca2+ levels, a mutant form carrying the GDD-causing T513I substitution showed PLS and large time-dependent ion currents even at low cytosolic Ca2+ concentrations. Contrarily, mutation of the homologous position in the Ca2+-activated Cl− channel TMEM16B paralog hardly affected its function. In summary, these data provide the first direct demonstration of Ca2+-dependent PLS activity for TMEM16E and suggest a gain-of-function phenotype related to a GDD mutation.
- Subjects
GENETIC mutation; DYSPLASIA; CELL transformation; CELLULAR pathology; PHOSPHOLIPIDS
- Publication
Cellular & Molecular Life Sciences, 2018, Vol 75, Issue 9, p1657
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-017-2704-9