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.SEC61A1is 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 outex vivoin primary cells of patients andin vitroin different cell lines to assess the effect ofSEC61A1mutations 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. Onin vitrostimulation, 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 inSEC61A1, 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.