MISSENSE MUTATION IN EXON-7 OF THE COMMON GAMMA-CHAIN GENE CAUSES A MODERATE FORM OF X-LINKED COMBINED IMMUNODEFICIENCY

Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma(c)) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status of X chromosome inactivation in blood leukocytes from obligate carriers of XCID was determined from the polymorphic, short tandem repeats (GAG), in the androgen receptor gene, which also contains a methylation-sensitive HpaII site. As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes. In addition, X chromosome inactivation in PMNs was variable. Findings from this analysis prompted sequencing of the gamma(c) gene in this pedigree. A missense mutation in the region coding for the cytoplasmic portion of the gamma(c) gene was found in three affected males but not in a normal brother. Therefore, this point mutation in the gamma(c) gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.