MUTATIONS OF JAK-3 GENE IN PATIENTS WITH AUTOSOMAL SEVERE COMBINED IMMUNE-DEFICIENCY (SCID)
MUTATIONS OF JAK-3 GENE IN PATIENTS WITH AUTOSOMAL SEVERE COMBINED IMMUNE-DEFICIENCY (SCID)
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DOI：
10.1038/377065a0
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发表时间：
1995-09-07
期刊：
影响因子：
64.8
通讯作者：
NOTARANGELO, LD
中科院分区：
文献类型：
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作者：
MACCHI, P;VILLA, A;NOTARANGELO, LD
严重联合免疫缺陷(SCID)是一组异质性遗传性疾病。常见的细胞因子受体包括白介素2、白介素4、白介素7、白介素9和白介素15，其共同的伽马链(γ(C))突变是X连锁SCID1、2的原因，通常与循环T细胞缺乏和B淋巴细胞(T-B+SCID)有关，导致常染色体隐性T-B+SCID的基因(S)尚不清楚，JAK-3蛋白激酶(3，4)已被发现与含有γ(C)链的细胞因子受体(4-9)相关。因此，JAK-3或与其相互作用(10，11)的STAT蛋白是常染色体隐性遗传T-B+SCID7的候选基因。在这里，我们调查了两名没有血缘关系的T-B+SCID患者(都来自血缘关系密切的父母)，他们的JAK-3基因都有纯合子突变。一名患者在Jak-3的JH7结构域的保守酪氨酸残基中携带突变(Tyr100-->；Cys)，该突变在150多条被研究的染色体中缺失。另一例患者的蛋白激酶样区存在151个碱基对的纯合缺失，导致移码和过早终止。这两个突变都导致Jak-3水平显著降低，这些发现表明Jak/STAT信号通路的异常可以解释人类SCID的原因。
SEVERE combined immune deficiency (SCID) represents a heterogenous group of hereditary diseases. Mutations in the common gamma-chain (gamma(c)), which is part of several cytokine receptors including those for interleukin (IL)-2, IL-4, IL-7, IL-9 and IL-15, are responsible for X-linked SCID1,2, which is usually(!ly associated with a lack of circulating T cells and the presence of B lymphocytes (T- B+ SCID), The gene(s) responsible for autosomal recessive T- B+ SCID is still unknown, The Jak-3 protein kinase(3,4) has been found to associate,vith the gamma(c)-chain-containing cytokine receptors(4-9). Therefore Jak-3 or other STAT proteins with which it interacts(10,11) are candidate genes for autosomal recessive T- B+ SCID7. Here we investigate two unrelated T- B+ SCID patients (both from consanguineous parents) who have homozygous mutations in the gene for Jak-3. One patient carries a mutation (Tyr100-->Cys) in a conserved tyrosine residue in the JH7 domain of Jak-3 which is absent in more than 150 investigated chromosomes. The other patient carries a homozygous 151-base-pair deletion in the kinase-like domain, leading to a frameshift and premature termination. Both mutations resulted in markedly reduced levels of Jak-3, These findings show that abnormalities in the Jak/STAT signalling pathway can account for SCID in humans.