Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1) - 05/04/18

Doi : 10.1016/j.jaci.2017.06.042

Desirée Schubert, PhD ^a,^b,^c, Marie-Christine Klein, MSc ^d, Sarah Hassdenteufel, MSc ^d, Andrés Caballero-Oteyza, PhD ^a, Linlin Yang, MD ^a, Michele Proietti, MD, PhD ^a, Alla Bulashevska, PhD ^a, Janine Kemming, MSc ^a, Johannes Kühn, MD ^a, Sandra Winzer, PhD ^a, Stephan Rusch ^a, Manfred Fliegauf, PhD ^a, Alejandro A. Schäffer, PhD ^e, Stefan Pfeffer, PhD ^f, Roger Geiger, PhD ^g,^h, Adolfo Cavalié, MD, PhD ⁱ, Hongzhi Cao, PhD ^j, Fang Yang, PhD ^j, Yong Li, PhD ^k, Marta Rizzi, MD ^l, Hermann Eibel, PhD ^a, Robin Kobbe, MD ^m, Amy L. Marks, DO ⁿ, Brian P. Peppers, DO, PhD ^o, Robert W. Hostoffer, DO, PhD ^o,^p, Jennifer M. Puck, MD ^q, Richard Zimmermann, PhD ^c, Bodo Grimbacher, MD ^a,^r,^⁎
^a Center for Chronic Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^l Department of Rheumatology and Clinical Immunology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^k Department of Medicine, Division of Nephrology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^b Spemann Graduate School of Biology and Medicine (SGBM), Faculty of Medicine, University of Freiburg, Freiburg, Germany
^c Faculty of Biology, University of Freiburg, Freiburg, Germany
^d Medical Biochemistry & Molecular Biology, Saarland University, Homburg, Germany
^e National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Md
^f Department of Molecular Structural Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany
^g Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
^h Institute of Microbiology, ETH Zürich, Zürich, Switzerland
ⁱ Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany
^j BGI-Shenzhen, Shenzhen, China
^m Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany
ⁿ Beaumont Children's Hospital Troy, Troy, Mich
^o University Hospitals Cleveland Medical Center, Allergy-Immunology Fellowship Program, Cleveland, Ohio
^p Allergy and Immunology Associates, Mayfield Heights, Ohio
^q Department of Pediatrics, University of California San Francisco School of Medicine and UCSF Benioff Children's Hospital, San Francisco, Calif
^r Institute of Immunity and Transplantation, UCL, London, United Kingdom

^∗Corresponding author: Bodo Grimbacher, MD, CCI-Center for Chronic Immunodeficiency, Universitätsklinikum Freiburg, Breisacherstraße 115, Freiburg 79106, Germany.CCI-Center for Chronic ImmunodeficiencyUniversitätsklinikum FreiburgBreisacherstraße 115Freiburg79106Germany

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.

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Key words : SEC61A1, translocon, protein translocation, antibody deficiency, plasma cell, multiple myeloma, calcium homeostasis, endoplasmic reticulum stress

Abbreviations used : ADTKD, ATF, BAFF, CD40L, CHOP, CVID, ER, IRE1A, IVIG, MM, PAD, PC, PERK, ppl, SEC61A1, siRNA, UPR, WT, XBP1s

Plan

Methods

Ethics approval

B-cell stimulation assay

SEC61A1 silencing and expression

Preprolactin processing and cytochrome B5 glycosylation

Live cell calcium imaging

Viral transduction of cell lines

Results

Clinical description of the families

Identification of heterozygous mutations in SEC61A1

The p.E381* nonsense mutation in family II leads to SEC61A1 haploinsufficiency

Affected subjects in both families have normal peripheral B- and T-cell subpopulations

B cells of mutation carriers have an intrinsic deficiency to develop into PCs

EBV-transformed B-cell lines carrying SEC61A1 mutations secrete less immunoglobulin

Protein translocation by the SEC61A1-V85D channel is impaired

Dissipation of the ER/cytosol calcium gradient in SEC61A1-V85D–producing HeLa cells

SEC61A1-V85D production selectively affects PCs

SEC61A1-V85D production and SEC61A1 knockdown induces the terminal UPR in PC lines

Dominant effect of mutant SEC61A1-V85D in sensitized HEK293T cells

Discussion

Supported by the Bundesministerium für Bildung und Forschung (BMBF) with grant nos. IFB/CCI: 01EO1303; E:med/SysInflame: 01ZX1306F, and DZIF: 8000805-3 (to B.G.) and supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School; to D.S.). This work was also supported in part by the Intramural Research Program of the National Institutes of Health, NLM (to A.A.S) and by grants from the Deutsche Forschungsgemeinschaft (to A.C. [SFB894] and R.Z. [IRTG1830, SFB894]).

Disclosure of potential conflict of interest: A. A. Schäffer is an employee of the National Institutes of Health, Intramural Research Program. M. Rizzi receives grant support form Novartis and Pfizer. R. Zimmermann receives grant support from Deutsche Forschungs-gemeinschaf. B. Grimbacher receives grant support from BMBF, the EU, Helmholtz, DFG, DLR, and DZIF; is an employee of UKL-FR; and receives payments for lectures from CSL-Behring, Baxalta, Shire, Biotest, Octopharma, Kedrion, and Grifols. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 141 - N° 4

P. 1427-1438 - avril 2018 Retour au numéro

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Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1) - 05/04/18

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