FEMALE GERM-LINE MOSAICISM AS THE ORIGIN OF A UNIQUE IL-2 RECEPTOR GAMMA-CHAIN MUTATION CAUSING X-LINKED SEVERE COMBINED IMMUNODEFICIENCY

The IL2RG gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human Xq13.1 and is mutated in males with X-linked sever e combined immunodeficiency (SCID). In a large Canadian pedigree genet ic linkage studies demonstrated that the proband's grandmother was the source of an X-linked SCID mutation. However, her T cells did not sho w the expected skewed X chromosome inactivation pattern of female carr iers of SCID, despite her having one affected son and two carrier daug hters' with skewed ii inactivation. Single strand conformation polymor phism analysis of IL2RG in the affected proband was abnormal in exon 5 ; sequencing revealed a nine nucleotide in-frame duplication insertion . The three duplicated amino acids included the first tryptophan of th e ''WSXWS'' motif found in all members of the;cytokine receptor gene s uperfamily. Mutation detection in the pedigree confirmed that the foun der grandmother's somatic cells had only normal IL2RG, and further sho wed that the SCID-associated X chromosome haplotype was inherited by t hree daughters, one with a wild type IL2RG gene and two others with th e insertional mutation. Female germ line mosaicism is unusual, but its presence in this X-linked SCID family emphasizes the limitations of g enetic diagnosis by linkage as compared with direct mutation analysis.