We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.

中文翻译：

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PAX1对于人类胸腺的发育和功能至关重要。

我们调查了6名2型耳面部宫颈综合症患者的严重联合免疫缺陷症（SCID）的分子和细胞基础，尽管他们成功移植了3个患者，但他们在异基因造血干细胞移植后未能实现T细胞重建。我们在所有患者中鉴定了罕见的双等位基因PAX1罕见变异。我们证明，这些突变的PAX1蛋白具有改变的构象和配对盒域的灵活性和减少的转录活性。我们产生了患者来源的诱导性多能干细胞，并将其分化为胸腺上皮祖细胞，发现它们的转录谱发生了变化，包括涉及胸腺和其他咽囊组织发育的基因。这些结果确定了双等位基因，