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26例非亲缘关系的X连锁无丙种球蛋白血症患者布鲁顿酪氨酸激酶基因的突变模式

Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia.

作者信息

Vorechovský I, Luo L, Hertz J M, Frøland S S, Klemola T, Fiorini M, Quinti I, Paganelli R, Ozsahin H, Hammarström L, Webster A D, Smith C I

机构信息

Karolinska Institute, Department of Biosciences, NOVUM, Huddinge, Sweden.

出版信息

Hum Mutat. 1997;9(5):418-25. doi: 10.1002/(SICI)1098-1004(1997)9:5<418::AID-HUMU7>3.0.CO;2-#.

Abstract

Mutation pattern was characterized in the Bruton's tyrosine kinase gene (BTK) in 26 patients with X-linked agammaglobulinemia, the first described immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations were found to result in premature termination of the translation product. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5' end of the gene and missense mutations in its 3' part, corresponding to the catalytic domain of the enzyme. Nonsense and frameshift mutations were associated with diminished levels of BTK mRNA expression, except for a frameshift mutation in exon 17 and two nonsense mutations in exon 2, indicating that these cases are not confined to penultimate exons. One amino acid substitution (R28H) was found in the pleckstrin homology domain's residue, which is mutated in mice bearing the X-linked immunodeficiency phenotype; another substitution (R307G) was identified in the src homology domain 2. All remaining amino acid substitutions were found in the catalytic domain of Btk.

摘要

对26例X连锁无丙种球蛋白血症患者的布鲁顿酪氨酸激酶基因(BTK)的突变模式进行了特征分析,X连锁无丙种球蛋白血症是首例被描述的免疫球蛋白缺乏症,其突变模式与BTK表达相关。共鉴定出24种不同的突变。大多数BTK突变被发现导致翻译产物提前终止。在大多数BTK外显子中检测到突变,基因5'端以移码突变和无义突变为主,3'部分以错义突变为主,对应于该酶的催化结构域。除了外显子17中的一个移码突变和外显子2中的两个无义突变外,无义突变和移码突变与BTK mRNA表达水平降低有关,这表明这些情况并不局限于倒数第二个外显子。在pleckstrin同源结构域的残基中发现了一个氨基酸替代(R28H),在具有X连锁免疫缺陷表型的小鼠中该残基发生了突变;在src同源结构域2中鉴定出另一个替代(R307G)。所有其余的氨基酸替代均在Btk的催化结构域中发现。

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