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Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome.

Authors
  • Agrebi, N1
  • Ben-Mustapha, I2
  • Matoussi, N3
  • Dhouib, N4
  • Ben-Ali, M5
  • Mekki, N6
  • Ben-Ahmed, M6
  • Larguèche, B7
  • Ben Becher, S3
  • Béjaoui, M4
  • Barbouche, M R6
  • Nourhen AGREBI
Type
Published Article
Journal
Clinical Immunology
Publisher
Elsevier
Publication Date
Sep 30, 2017
Volume
183
Pages
17–23
Identifiers
DOI: 10.1016/j.clim.2017.06.009
PMID: 28668589
Source
Medline
Keywords
License
Unknown

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis characterized by autoimmune features and lymphoproliferation. Heterozygous germline or somatic FAS mutations associated with preserved protein expression have been described. Very rare cases of homozygous germline FAS mutations causing severe autosomal recessive form of ALPS with a complete defect of Fas expression have been reported. We report two unrelated patients from highly inbred North African population showing a severe ALPS phenotype and an undetectable Fas surface expression. Two novel homozygous mutations have been identified underlying rare splicing defects mechanisms. The first mutation breaks a branch point sequence and the second alters a regulatory exonic splicing site. These splicing defects induce the skipping of exon 6 encoding the transmembrane domain of CD95. Our findings highlight the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing and illustrate the importance of such studies in highly consanguineous populations.

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