PAX1 is essential for development and function of the human thymus

Abstract

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.

T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

“…In one of the cases with successful engraftment all the T cells showed a memory (CD45R0+) phenotype, but no de novo generation of a polyclonal repertoire of naive T cells was observed. The remaining 2 patients showed persistent T cell lymphopenia leading to severe and recurrent infections, and death for septic shock in one patient and to severe autoimmune hemolytic anemia in the other (74). Together, these data indicate that HSCT may be unable to correct the profound T cell immunodeficiency of this disease.…”

“…Two different forms of OTFCS have been described but thymus development is only affected in OTFCS2, caused by PAX1 mutations. Different biallelic deleterious PAX1 variants cause OTFCS2 and SCID, characterized by absent thymic shadow, chronic diarrhea, recurrent respiratory infections, pneumonia, and also Omenn Syndrome (74). Different severity of OTFCS2 phenotype is described in different families (70,71,77).…”

“…Lymph node biopsy of another patient showed absence of germinal centers and almost total absence of CD3+ T cells. Patients with Omenn Syndrome also showed eosinophilia and increased IgE levels (74).…”

“…Chd7 deficiency is also associated with down-regulation of Ikaros, Interelukin 7 receptor (Il7r), recombinase activating gene 1 (Rag1) (124). Studies suggest that CHD7 can also regulate TBX1 expression (74,125). CHARGE syndrome is characterized by different degrees of thymic alterations and even by complete thymic aplasia, resulting in combined immune deficiency (126).…”

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

“…Patients with PAX1 mutations can present with otofaciocervical syndrome type 2 and SCID. Some patients with mutations affecting PAX1 DNA binding and transcriptional regulation activities fail to reconstitute their T cell compartments following otherwise successful HSCT [45]. T cells from these patients were hypofunctional.…”