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.

中文翻译：

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具有Sec61 translocon alpha 1亚基（SEC61A1）杂合突变的人类受试者的浆细胞缺乏症

背景

原发性抗体缺陷（PAD）是人类受试者中最常见的原发性免疫缺陷。PAD的遗传原因在很大程度上是未知的。Sec61 translocon alpha 1亚基（SEC61A1）是Sec61复合物的主要亚基，Sec61复合物是内质网膜中主要的多肽传导通道。SEC61A1是剪接的X-box结合蛋白1的靶基因，在浆细胞（PC）分化过程中被强烈诱导。

客观的

我们鉴定了一种新的遗传缺陷，并研究了来自2个无关家族的PAD的11例患者的病理机制。

方法

进行了全外显子和靶向测序以鉴定新的基因突变。在患者的原代细胞中进行体内研究，并在不同细胞系中进行体外研究，以评估SEC61A1突变对B细胞分化和存活的影响。

结果

我们调查了2个患有低球蛋白血症，严重反复呼吸道感染以及正常外周B细胞和T细胞亚群的患者的家庭。在体外的刺激，B细胞表现出固有的缺陷发展成电脑。遗传分析和鉴定的新型杂合错义（c.254T> A，p.V85D）和无义靶向测序（c.1325G> T，p.E381 *）在突变SEC61A1，与疾病表型分离。SEC61A1-V85D缺乏共翻译蛋白易位，并扰乱了HeLa细胞的细胞钙稳态。此外，SEC61A1-V85D在多种骨髓瘤细胞系中触发了最终的未折叠蛋白反应。

结论

我们描述了导致人类受试者特定PC缺乏的单基因缺陷，从而扩展了我们对抗体缺陷发病机理的认识。