Research ArticleTHYMUS

PAX1 is essential for development and function of the human thymus

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Science Immunology  28 Feb 2020:
Vol. 5, Issue 44, eaax1036
DOI: 10.1126/sciimmunol.aax1036

PAX1 in the thymus

Severe combined immunodeficiency (SCID) encompasses a wide spectrum of genetic disorders. Here, Yamazaki et al. have studied immune deficits in six patients with otofaciocervical syndrome type 2, a genetic abnormality attributed to biallelic mutations in PAX1. In addition to immunodeficiency, the disease is also characterized by facial dysmorphism, hearing loss and skeletal abnormalities. The patients were subjected to hematopoietic stem cell transplantation to rectify their immunodeficiency. Despite successful engraftment in three of these patients, all three of them failed to develop T cells. By generating patient-derived induced pluripotent stem cells and differentiating then ex vivo into thymic epithelial progenitors (TEPs), the authors find that PAX1 plays an important role in regulating the development of TEPs.


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.

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