Human JAK1 is involved in multiple cytokine responsive pathways, including type I and II IFN signalling pathways. Homozygosity for a rare germline hypomorphic mutation in JAK1 was previously described in a 22-year-old Pakistani patient with mycobacterial and viral infections, as well as early onset bladder malignancy.
By whole-exome sequencing, we investigated a 6-year-old Algerian patient with mycobacterial infections mimicking Langerhans histiocytiosis.
The patient is compound heterozygous for a missense (p.C657S) and a splice mutation (c.2108_2115+15del) in JAK1. The splice mutant allele encodes three alternative transcripts (c.1756_2115del, c.1900_2115del, and c.1988_2115del). Upon overexpression, the missense protein impairs but does not abolish responses to IFN-γ, while it does not even impair responses to IFN-α2b. In contrast, the products of the three splice variants are loss-of-function for both IFN-γ and IFN-α2b stimulation. Moreover, EBV-B cells from the patient respond poorly to IFN-γ, a phenotype that is rescued by retrotransduction with a WT JAK1 cDNA. Response to IFN-α2b is normal in EBV-B cells from patient. In contrast, the patient’s fibroblasts respond normally to both IFN-γ and IFN-α2b.
We thus describe a second patient with a novel partial form of autosomal recessive JAK1 deficiency, manifesting as isolated MSMD due to an apparently selective impairment of the IFN-γ responsive pathway.