Plasma cell deficiency in humans with heterozygous mutations in SEC61A1

Publication date: Available online 4 August 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés Caballero-Oteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A. Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Yong Li, Marta Rizzi, Hermann Eibel, Robin Kobbe, Amy L. Marks, Brian P. Peppers, Robert W. Hostoffer, Jennifer M. Puck, Richard Zimmermann, Bodo Grimbacher
BackgroundPrimary antibody deficiencies (PAD) are the most frequent primary immunodeficiencies in humans. The genetic causes for 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 (ER) membrane. SEC61A1 is a target gene of XBP1s and strongly induced during plasma cell differentiation.ObjectiveCharacterization of a novel genetic defect and its pathological mechanism in eleven patients from two unrelated families with PAD.MethodsWhole exome sequencing (WES) 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.ResultsWe investigated two families with patients suffering from hypogammaglobulinemia, severe recurrent respiratory tract infections and normal peripheral B- and T cell subpopulations. Upon in vitro stimulation, B cells showed an intrinsic deficiency to develop into plasma cells (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 co-translational protein translocation and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response (UPR) in multiple myeloma (MM) cell lines.ConclusionWe describe a monogenic defect leading to a specific plasma cell deficiency in humans, expanding our knowledge about the pathogenesis of antibody deficiencies.

Teaser

Heterozygous mutations in SEC61A1 are associated with plasma cell deficiency in patients with early-onset hypogammaglobulinemia and severe, recurrent respiratory tract infections but with normal B cell subpopulations in the peripheral blood.


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