JAK3 – T-B+ Severe Combined Immunodeficiency due to JAK3 Deficiency

Autosomal recessive loss-of-function mutations in JAK3 (HGNC:6193) cause T-B+ severe combined immunodeficiency (MONDO:0010938), characterized by profound T- and NK-cell lymphopenia with preserved B cells. A total of 33 unrelated probands with biallelic JAK3 variants have been reported ([PMID:11668610], [PMID:14615376]), supporting a definitive gene–disease association.

Genetic Evidence

Patients present with T(–)B(+)NK(–) immunophenotypes and recurrent infections, often following live vaccine administration. Compound heterozygous and homozygous variants affecting all seven JH domains include missense, nonsense, splice-site, and frameshift alleles. One recurrent variant is c.1744C>T (p.Arg582Trp). Segregation analysis in consanguineous families confirms autosomal recessive inheritance, although extended pedigrees are limited.

Functional Evidence

Jak3–/– mice recapitulate the human phenotype, exhibiting severe T and B lymphoid defects and absent NK cells ([PMID:8777722]). In vitro retroviral transduction of wild-type JAK3 into patient-derived cells restores IL-2- and IL-4-induced STAT5 phosphorylation and cellular proliferation ([PMID:8676091]). These concordant models establish JAK3 haploinsufficiency as the underlying mechanism.

Clinical Implications

Genetic testing for JAK3 variants should be included in newborn SCID screening panels. Definitive molecular diagnosis guides early hematopoietic stem cell transplantation and informs family counseling. Functional assays of JAK3 phosphorylation can expedite diagnosis.

Key Take-home: JAK3 deficiency is a definitive autosomal recessive cause of T-B+ SCID, with robust genetic and functional validation supporting its use in diagnostic and therapeutic decision-making.

References

• Human mutation • 2001 • Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. [PMID:11668610]
• Blood • 2004 • Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. [PMID:14615376]
• Immunity • 1995 • Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. [PMID:8777722]
• The Journal of experimental medicine • 1996 • In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction. [PMID:8676091]

Evidence Based Scoring (AI generated)