Jacinta Bustamante, FranceParis Descartes University-INSERM UMR1163- Laboratory of Human Genetics of Infectious Diseases
Presenter Of 2 Presentations
MYCOBACTERIAL DISEASE DUE TO INHERITED IFN-G DEFICIENCY
Background and Aims
Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by severe infections by BCG vaccines and environmental mycobacteria in otherwise healthy individuals. Isolated or syndromic MSMD is caused by inborn errors of IFN-γ immunity, with mutations in 15 genes that control the production of, or the response to IFN-γ. Whereas a lot of mutations has been reported in IFNGR1 and IFNGR2 genes, mutations in the IFN-γ cytokine itself have not been reported.
By whole exome-sequencing, we set out to search for mutations in IFNG among patients with unexplained isolated or syndromic MSMD referred to our laboratory.
We identified two Lebanese cousins who are both homozygous for a small deletion c.354_357del mutation in the IFNG gene causing a framesfhit p.T119Ifs4* which generates a premature stop codon. In overexpression system, the mutant allele encodes a truncated protein. T-saimiri lymphocytes had undetectable secretion of IFN-γ, which could be rescued by retrotransduction with WT-IFNG allele. Their primary lymphocytes failed to express and secrete detectable IFN-γ Moreover, IFNG has evolved under purifying selection unlike its two receptors, and suggest that IFNG can be less tolerant to heterozygous mutations than IFNGR1 and IFNGR2.
We thus identified and characterized a novel form of MSMD due to an autosomal recessive, complete IFN-g deficiency. This is the first characterization of a human deficiency in IFN-γ, the key cytokine necessary for the control of Mycobacteria and extends previous results performed in mice.
MYCOBACTERIAL DISEASE MIMICKING LANGERHANS HISTIOCYTOSIS IN A PATIENT WITH A NOVEL FORM OF INHERITED JAK1 DEFICIENCY
Background and Aims
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.