PAX1 is essential for development and function of the human thymus

Sci Immunol. 2020 Feb 28;5(44):eaax1036. doi: 10.1126/sciimmunol.aax1036.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Branchio-Oto-Renal Syndrome / genetics
  • Branchio-Oto-Renal Syndrome / immunology
  • Branchio-Oto-Renal Syndrome / pathology
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology
  • Humans
  • Infant
  • Male
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / immunology*
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / pathology
  • Thymus Gland / immunology*
  • Thymus Gland / pathology


  • Paired Box Transcription Factors
  • PAX1 transcription factor