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Novel ORAI1 Mutation Disrupts Channel Trafficking Resulting in Combined Immunodeficiency

Version 2 2024-11-12, 11:42
Version 1 2022-11-22, 21:13
journal contribution
posted on 2024-11-12, 11:42 authored by Fang Yu, Nourhen Agrebi, Rafah Mackeh, Khaled Abouhazima, Khadija KhudaBakhsh, Mehdi Adeli, Bernice Lo, Amel Hassan, Khaled Machaca

Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient’s lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.

Other Information

Published in: Journal of Clinical Immunology
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: http://dx.doi.org/10.1007/s10875-021-01004-8

Funding

Open access funding provided by the Qatar National Library.

Qatar National Research Fund (PPM 04-0128-200015), Unlocking precision medicine potential through functional genomic studies in the diagnosis of inherited immunodeficiency diseases.

History

Language

  • English

Publisher

Springer Nature

Publication Year

  • 2021

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Weill Cornell Medicine - Qatar
  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine