Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
Antigens, CD34
/ metabolism
Chromosome Disorders
Congenital Bone Marrow Failure Syndromes
/ genetics
Female
Genes, Dominant
HL-60 Cells
Humans
Mutation
/ genetics
Neutropenia
/ congenital
Neutrophils
/ physiology
Pedigree
SEC Translocation Channels
/ genetics
Single-Cell Analysis
Unfolded Protein Response
/ genetics
Exome Sequencing
Young Adult
SEC61A1
Severe congenital neutropenia
endoplasmic reticulum stress
unfolded protein response
whole exome sequencing
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
21
10
2019
revised:
24
03
2020
accepted:
27
03
2020
pubmed:
24
4
2020
medline:
16
3
2021
entrez:
24
4
2020
Statut:
ppublish
Résumé
The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease. Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN. Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2 We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34 Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.
Sections du résumé
BACKGROUND
The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease.
OBJECTIVE
Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN.
METHODS
Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2
RESULTS
We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34
CONCLUSION
Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.
Identifiants
pubmed: 32325141
pii: S0091-6749(20)30488-7
doi: 10.1016/j.jaci.2020.03.034
pmc: PMC7649975
pii:
doi:
Substances chimiques
Antigens, CD34
0
SEC Translocation Channels
0
SEC61A1 protein, human
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1180-1193Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BBS/E/B/000C0427
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BBS/E/B/000C0428
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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