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

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 4; pp. 1427 - 1438
• Main Authors: Schubert, Desirée, Klein, Marie-Christine, Hassdenteufel, Sarah, Caballero-Oteyza, Andrés, Yang, Linlin, Proietti, Michele, Bulashevska, Alla, Kemming, Janine, Kühn, Johannes, Winzer, Sandra, Rusch, Stephan, Fliegauf, Manfred, Schäffer, Alejandro A., Pfeffer, Stefan, Geiger, Roger, Cavalié, Adolfo, Cao, Hongzhi, Yang, Fang, Li, Yong, Rizzi, Marta, Eibel, Hermann, Kobbe, Robin, Marks, Amy L., Peppers, Brian P., Hostoffer, Robert W., Puck, Jennifer M., Zimmermann, Richard, Grimbacher, Bodo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018; Elsevier Limited
• Subjects: Activating transcription factor 1; Agammaglobulinemia - genetics; Agammaglobulinemia - metabolism; Agammaglobulinemia - pathology; antibody deficiency; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Calcium - metabolism; Calcium homeostasis; Cell Differentiation - genetics; Cell Line; Cell Line, Tumor; Cell lines; Diabetes; Disease; Endoplasmic reticulum; endoplasmic reticulum stress; Ethics; Exome - genetics; Genes; Genetic analysis; Genotype & phenotype; HEK293 Cells; HeLa Cells; Heterozygote; Homeostasis; Human subjects; Humans; Hypogammaglobulinemia; Immunoglobulins; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - metabolism; Kinases; Laboratories; Lymphocytes B; Lymphocytes T; Multiple myeloma; Mutation; Mutation - genetics; Phenotypes; plasma cell; Plasma Cells - metabolism; Plasma Cells - pathology; Plasmids; Polypeptides; Primary immunodeficiencies; Protein folding; Protein synthesis; protein translocation; Protein transport; Protein Transport - genetics; Proteins; Respiratory tract diseases; Respiratory Tract Infections - genetics; Respiratory Tract Infections - metabolism; Respiratory Tract Infections - pathology; SEC Translocation Channels - genetics; SEC61A1; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; translocon; Tumor cell lines; Unfolded Protein Response - genetics; Germany; CD40L; IRE1A; antibody deficiency; PERK; endoplasmic reticulum stress; protein translocation; SEC61A1; CVID; translocon; UPR; CHOP; plasma cell; WT; ADTKD; MM; BAFF; multiple myeloma; IVIG; calcium homeostasis; siRNA; ER; ppl; PAD; ATF; PC; XBP1s
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.06.042

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. We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs. 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. 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. We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.