Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1)
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Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). / 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.
in: J ALLERGY CLIN IMMUN, 04.08.2017.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1)
AU - Schubert, Desirée
AU - Klein, Marie-Christine
AU - Hassdenteufel, Sarah
AU - Caballero-Oteyza, Andrés
AU - Yang, Linlin
AU - Proietti, Michele
AU - Bulashevska, Alla
AU - Kemming, Janine
AU - Kühn, Johannes
AU - Winzer, Sandra
AU - Rusch, Stephan
AU - Fliegauf, Manfred
AU - Schäffer, Alejandro A
AU - Pfeffer, Stefan
AU - Geiger, Roger
AU - Cavalié, Adolfo
AU - Cao, Hongzhi
AU - Yang, Fang
AU - Li, Yong
AU - Rizzi, Marta
AU - Eibel, Hermann
AU - Kobbe, Robin
AU - Marks, Amy L
AU - Peppers, Brian P
AU - Hostoffer, Robert W
AU - Puck, Jennifer M
AU - Zimmermann, Richard
AU - Grimbacher, Bodo
N1 - Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.
PY - 2017/8/4
Y1 - 2017/8/4
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1016/j.jaci.2017.06.042
DO - 10.1016/j.jaci.2017.06.042
M3 - SCORING: Journal article
C2 - 28782633
JO - J ALLERGY CLIN IMMUN
JF - J ALLERGY CLIN IMMUN
SN - 0091-6749
ER -