Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain–containing 3 ( NUDCD3 ) . Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T - B - SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.

中文翻译：

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NUDCD3 缺陷会破坏 V(D)J 重组，导致 SCID 和 Omenn 综合征


T 细胞发育的先天性缺陷是一种儿科急症，需要通过分子诊断及时进行治疗。在 4 个近亲亲属的 11 名受影响患者中，我们检测到含 NudC 结构域 3 (NUDCD3) 基因中单个有害错义变异的纯合性。两名婴儿患有严重联合免疫缺陷，完全缺乏 T 细胞和 B 细胞 (T - B - SCID) ），而九个表现出奥门综合征（OS）的经典特征。残留 T 淋巴细胞限制抗原受体基因使用表明 V(D)J 重组受损。患者细胞的 NUDCD3 蛋白表达减少，支持 RAG 介导的体外重组的能力减弱，这与核仁中 RAG1 的病理性隔离有关。尽管携带同源变异的小鼠模型中 V(D)J 重组受损会导致较轻微的免疫异常，但 NUDCD3 对于人类 T 和 B 细胞的健康发育绝对是必需的。