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Defective Sec61?1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

ABSTRACT: BACKGROUND:The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the ?-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+ flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, quantitative PCR for unfolded protein response (UPR) genes, and single-cell RNA sequencing on whole bone marrow. 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+ cells recapitulated the patient's clinical arrest in granulopoiesis. The impact of Q92R-Sec61?1 on neutrophil maturation was validated by using HL-60 cells, in which transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34+ cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes. CONCLUSION:Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.

SUBMITTER: Van Nieuwenhove E 

PROVIDER: S-EPMC7649975 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

Van Nieuwenhove Erika E   Barber John S JS   Neumann Julika J   Smeets Elien E   Willemsen Mathijs M   Pasciuto Emanuela E   Prezzemolo Teresa T   Lagou Vasiliki V   Seldeslachts Laura L   Malengier-Devlies Bert B   Metzemaekers Mieke M   Haßdenteufel Sarah S   Kerstens Axelle A   van der Kant Rob R   Rousseau Frederic F   Schymkowitz Joost J   Di Marino Daniele D   Lang Sven S   Zimmermann Richard R   Schlenner Susan S   Munck Sebastian S   Proost Paul P   Matthys Patrick P   Devalck Christine C   Boeckx Nancy N   Claessens Frank F   Wouters Carine C   Humblet-Baron Stephanie S   Meyts Isabelle I   Liston Adrian A  

The Journal of allergy and clinical immunology 20200420 5

<h4>Background</h4>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.<h4>Objective</h4>Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN.<  ...[more]

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