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Mutation analysis of IL2RG in human X-linked severe combined
immunodeficiency
JM Puck, AE Pepper, PS Henthorn, F Candotti, J Isakov, T Whitwam, ME Conley, RE Fischer, HM Rosenblatt, TN Small and RH Buckley
Laboratory for Gene Transfer, National Center for Human Genome Research,
Bethesda, MD 20892-4442, USA.
Severe combined immunodeficiency (SCID) is a syndrome of profoundly
impaired cellular and humoral immunity. In humans, SCID is most commonly
caused by mutations in the X-linked gene IL2RG, which encodes the common
gamma chain, gamma c, of the leukocyte receptors for interleukin-2 and
multiple other cytokines. To investigate the frequency and variety of IL2RG
mutations that cause SCID, we analyzed DNA, RNA, and B-cell lines from a
total of 103 unrelated SCID-affected males and their relatives using a
combination of molecular and immunologic techniques. Sixty-two different
mutations spanning all eight IL2RG exons were found in 87 cases, making
possible correlations between mutation type and functional consequences.
Although skewed maternal X chromosome inactivation, single-strand
conformation polymorphism, mRNA expression, and cell surface staining with
anti- gamma c antibodies were all helpful in establishing IL2RG defects as
the cause of SCID, only dideoxy fingerprinting and DNA sequence
determination each detected 100% of the IL2RG mutations in our series.
Abnormal gamma c chains may be expressed in the lymphocytes of as many as
two thirds of patients with X-linked SCID. Specific mutation diagnosis thus
remains technically challenging, but it is important for genetic counseling
and perhaps for helping to select appropriate subjects for retroviral gene
therapy trials, This is a US government work. There are no restrictions on
its use.
Volume 89,
Issue 6,
pp. 1968-1977,
03/15/1997
Copyright © 1997 by The American Society of Hematology
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