Science immunology · 2020
PAX1 is essential for development and function of the human thymus.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
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Yamazaki Yasuhiro, Urrutia Raul, Franco Luis M, Giliani Silvia, Zhang Kejian, Alazami Anas M, Dobbs A Kerry, Masneri Stefania, Joshi Avni, Otaizo-Carrasquero Francisco, Myers Timothy G, Ganesan Sundar, Bondioni Maria Pia, Ho Mai Lan, Marks Catherine, Alajlan Huda, Mohammed Reem W, Zou Fanggeng, Valencia C Alexander, Filipovich Alexandra H, Facchetti Fabio, Boisson Bertrand, Azzari Chiara, Al-Saud Bander K, Al-Mousa Hamoud, Casanova Jean Laurent, Abraham Roshini S, Notarangelo Luigi D
Аннотация
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.