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Novel disease loci
Original research
TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents
  1. Julien H Park1,
  2. Jiraporn Ousingsawat2,
  3. Inês Cabrita2,
  4. Ruth E Bettels1,
  5. Jörg Große-Onnebrink1,
  6. Christian Schmalstieg1,
  7. Saskia Biskup3,
  8. Janine Reunert1,
  9. Stephan Rust1,
  10. Rainer Schreiber2,
  11. Karl Kunzelmann2,
  12. Thorsten Marquardt1
  1. 1 Department of Paediatrics, University Hospital Münster, Münster, Nordrhein-Westfalen, Germany
  2. 2 Department of Physiology, University of Regensburg, Regensburg, Bayern, Germany
  3. 3 CeGaT GmbH, Tübingen, Baden-Württemberg, Germany
  1. Correspondence to Dr Thorsten Marquardt, Department of Paediatrics, University Hospital Münster, 48149 Münster, Germany; marquat{at}uni-muenster.de

Abstract

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.

  • genetics
  • gastroenterology
  • pediatrics

https://doi.org/10.1136/jmedgenet-2020-106978

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    Footnotes

    • JHP and JO are joint first authors.

    • KK and TM are joint senior authors.

    • Contributors JHP, JO, KK and TM conceived and designed the experiments and performed the data analysis. JHP, KK and TM wrote the manuscript. JO, IC, RS and KK performed electrophysiological as well as immunohistological studies. JHP, REB, JG-O, CS and TM collected clinical data and samples. Genetic studies were performed by SB, JR and SR.

    • Funding This study was supported by DFG Projektnummer 387509280–SFB 1350, DFG KU756/14-1, and Cystic Fibrosis Trust SRC 013.

    • Competing interests None declared.

    • Patient consent for publication Parental/guardian consent obtained.

    • Ethics approval The study was approved by the institutional review board of the Children’s University Hospital Münster (Ethikkommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Univeristät Münster) under the reference 2019–482f-S.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. All data presented in this article are available from the corresponding author upon reasonable request.