SOMATIC MOSAICISM FOR A NEWLY IDENTIFIED SPLICE-SITE MUTATION IN A PATIENT WITH ADENOSINE DEAMINASE-DEFICIENT IMMUNODEFICIENCY AND SPONTANEOUS CLINICAL RECOVERY

Absent or severely reduced adenosine deaminase (ADA) activity produces inherited immunodeficiency of varying severity, with defects of both cellular and humoral immunity. We report somatic mosaicism as the basi s for a delayed presentation and unusual course of a currently healthy young adult receiving no therapy. He was diagnosed at age 2 1/2 years because of life-threatening pneumonia, recurrent infections, failure of normal growth, and lymphopenia, but he retained significant cellula r immune function. A fibroblast cell line and a B cell line, establish ed at diagnosis, lacked ADA activity and were heteroallelic for a spli ce-donor-site mutation in IVS 1 (+1GT-->CT) and a missense mutation (A rg101Gln). All clones (17/17) isolated from the B cell mRNA carried th e missense mutation, indicating that the allele with the splice-site m utation produced unstable mRNA. In striking contrast, a B cell line es tablished at age 16 years expressed 50% of normal ADA; 50% of ADA mRNA had normal sequence, and 50% had the missense mutation. Genomic DNA c ontained the missense mutation but not the splice-site mutation. All t hree cell lines were identical for multiple polymorphic markers and th e presence of a Y chromosome. In vivo somatic mosaicism was demonstrat ed in genomic DNA from peripheral blood cells obtained at 16 years of age, in that less than half the DNA carried the splice-site mutation ( P<.002, vs. original B cell line). Consistent with mosaicism, erythroc yte content of the toxic metabolite deoxyATP was only minimally elevat ed. Somatic mosaicism could have arisen either by somatic mutation or by reversion at the site of mutation. Selection in vivo for ADA normal hematopoietic cells may have played a role in the return to normal he alth, in the absence of therapy.