RT Journal Article
SR Electronic
T1 TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 247
OP 253
DO 10.1136/jmedgenet-2020-106978
VO 58
IS 4
A1 Park, Julien H
A1 Ousingsawat, Jiraporn
A1 Cabrita, Inês
A1 Bettels, Ruth E
A1 Große-Onnebrink, Jörg
A1 Schmalstieg, Christian
A1 Biskup, Saskia
A1 Reunert, Janine
A1 Rust, Stephan
A1 Schreiber, Rainer
A1 Kunzelmann, Karl
A1 Marquardt, Thorsten
YR 2021
UL http://jmg.bmj.com/content/58/4/247.abstract
AB Introduction TMEM16A is a calcium-activated chloride channel expressed in various secretory epithelia. Two siblings presented in early infancy with reduced intestinal peristalsis and recurrent episodes of haemorrhagic diarrhoea. In one of them, the episodes were characterised by hepatic pneumatosis with gas bubbles in the portal vein similar to necrotising enterocolitis of the newborn.Methods Exome sequencing identified a homozygous truncating pathogenic variant in ANO1. Expression analysis was performed using reverse transcription PCR, western blot and immunohistochemistry. Electrophysiological and cell biological studies were employed to characterise the effects on ion transport both in patient respiratory epithelial cells and in transfected HEK293 cells.Results The identified variant led to TMEM16A dysfunction, which resulted in abolished calcium-activated Cl− currents. Secondarily, CFTR function is affected due to the close interplay between both channels without inducing cystic fibrosis (CF).Conclusion TMEM16A deficiency is a potentially fatal disorder caused by abolished calcium-activated Cl− currents in secretory epithelia. Secondary impairment of CFTR function did not cause a CF phenotyp, which may have implications for CF treatment.