Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency.
The IL-2R gamma-chain is an indispensable subunit for the functional IL-2R. Recently, mutations of the gamma-chain have been reported to be closely associated with X-linked severe combined immunodeficiency (XSCID). The present study reveals that three patients with XSCID have three different mutations in the gamma-chain; a point mutation, a two consecutive-base deletion, and lack of the second exon in mRNA. The point mutation that we have detected is C to T, which results in one amino acid substitution of valine for alanine in the extracellular domain of the IL-2R gamma-chain (named AV mutant). The two-base deletion detected causes a frame shift of the coding region in the SH2 subdomain in the cytoplasmic domain (named tSH mutant). Transfection studies performed with the mutant gamma-chains demonstrated that the AV mutant and tSH mutant failed to bind to IL-2 and to transduce growth signals, respectively. These findings indicate that the gamma-chain gene mutations that accompany XSCID induce loss of the gamma-chain function, possibly resulting in stagnation of the differentiation and development of T cells.
Ishii
N
N
Department of Microbiology, Tohoku University School of Medicine, Sendai, Japan.
Asao
H
H
Kimura
Y
Y
Takeshita
T
T
Nakamura
M
M
Tsuchiya
S
S
Konno
T
T
Maeda
M
M
Uchiyama
T
T
Sugamura
K
K
D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D016762:Genes, fos; D016758:Genes, jun; D016259:Genes, myc; D006801:Humans; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D015398:Signal Transduction
D017931:DNA Primers; D008024:Ligands; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2