PAX1 is essential for development and function of the human thymus

Area of Science:

• Immunology
• Genetics
• Developmental Biology

Background:

• Severe combined immunodeficiency (SCID) impairs T cell development, leading to profound immune deficiency.
• Otofaciocervical syndrome type 2 is a rare genetic disorder with complex phenotypes.
• Understanding the genetic basis of SCID is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the molecular and cellular basis of SCID in patients with otofaciocervical syndrome type 2.
• To identify the genetic cause of T cell non-reconstitution after hematopoietic stem cell transplantation in these patients.

Main Methods:

• Genetic analysis to identify mutations in six SCID patients.
• Protein analysis to assess the function of mutant PAX1.
• Generation and differentiation of patient-derived induced pluripotent stem cells (iPSCs).
• Analysis of transcriptional profiles in differentiated cells.

Main Results:

• Identified rare biallelic PAX1 variants in all studied patients.
• Mutant PAX1 proteins exhibited altered conformation, flexibility, and reduced transcriptional activity.
• Patient-derived thymic epithelial progenitor cells showed altered transcriptional profiles, affecting thymus development.
• SCID was linked to impaired thymus development due to PAX1 dysfunction.

Conclusions:

• Biallelic, loss-of-function PAX1 mutations cause a syndromic form of SCID.
• PAX1 is essential for thymus development and T cell generation.
• This discovery provides a molecular explanation for SCID in otofaciocervical syndrome type 2.