MUTATION ANALYSIS OF IL2RG IN HUMAN X-LINKED SEVERE COMBINED IMMUNODEFICIENCY

Severe combined immunodeficiency (SCID) is a syndrome of profoundly im paired cellular and humoral immunity. In humans, SCID is most commonly caused by mutations in the X-linked gene IL2RG, which encodes the com mon gamma chain, gamma, of the leukocyte receptors for interleukin-alp ha and multiple other cytokines, To investigate the frequency and vari ety of IL2RG mutations that cause SCID, we analyzed DNA, RNA, and B-ce ll lines from a total of 103 unrelated SCID-affected males and their r elatives using a combination of molecular and immunologic techniques, Sixty-two different mutations spanning all eight IL2RG exons were foun d in 87 cases, making possible correlations between mutation type and functional consequences. Although skewed maternal X chromosome inactiv ation, single-strand conformation polymorphism, mRNA expression, and c ell surface staining with anti-gamma c antibodies were all helpful in establishing IL2RG defects as the cause of SCID, only dideoxy fingerpr inting and DNA sequence determination each detected 100% of the IL2RG mutations in our series, Abnormal gamma c chains may be expressed in t he lymphocytes of as many as two thirds of patients with X-linked SCID . Specific mutation diagnosis thus remains technically challenging, bu t it is important for genetic counseling and perhaps for helping to se lect appropriate subjects for retroviral gene therapy trials.