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J Allergy Clin Immunol. 2018 Apr;141(4):1427-1438. doi: 10.1016/j.jaci.2017.06.042. Epub 2017 Aug 4.

Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).

Author information

1
Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
2
Medical Biochemistry & Molecular Biology, Saarland University, Homburg, Germany.
3
Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Md.
5
Department of Molecular Structural Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany.
6
Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland; Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
7
Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
8
BGI-Shenzhen, Shenzhen, China.
9
Department of Medicine, Division of Nephrology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
10
Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
11
Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany.
12
Beaumont Children's Hospital Troy, Troy, Mich.
13
University Hospitals Cleveland Medical Center, Allergy-Immunology Fellowship Program, Cleveland, Ohio.
14
University Hospitals Cleveland Medical Center, Allergy-Immunology Fellowship Program, Cleveland, Ohio; Allergy and Immunology Associates, Mayfield Heights, Ohio.
15
Department of Pediatrics, University of California San Francisco School of Medicine and UCSF Benioff Children's Hospital, San Francisco, Calif.
16
Faculty of Biology, University of Freiburg, Freiburg, Germany.
17
Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Immunity and Transplantation, UCL, London, United Kingdom. Electronic address: bodo.grimbacher@uniklinik-freiburg.de.

Abstract

BACKGROUND:

Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X-box binding protein 1 and strongly induced during plasma cell (PC) differentiation.

OBJECTIVE:

We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs.

METHODS:

Whole-exome and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B-cell differentiation and survival.

RESULTS:

We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations. On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs. Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response in multiple myeloma cell lines.

CONCLUSION:

We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.

KEYWORDS:

SEC61A1; antibody deficiency; calcium homeostasis; endoplasmic reticulum stress; multiple myeloma; plasma cell; protein translocation; translocon

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