A MISSENSE MUTATION OF THE ENDOTHELIN-B RECEPTOR GENE IN MULTIGENIC HIRSCHSPRUNGS-DISEASE
A MISSENSE MUTATION OF THE ENDOTHELIN-B RECEPTOR GENE IN MULTIGENIC HIRSCHSPRUNGS-DISEASE
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DOI：
10.1016/0092-8674(94)90016-7
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发表时间：
1994-12-30
期刊：
影响因子：
64.5
通讯作者：
CHAKRAVARTI, A
中科院分区：
文献类型：
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作者：
PUFFENBERGER, EG;HOSODA, K;CHAKRAVARTI, A
先天性巨结肠 (HSCR) 的特征是远端结肠中肠神经节的缺失以及胃肠道神经支配的失败。我们最近将隐性易感基因座 (HSCR2) 定位到人类染色体 13q22，现在我们证明它是内皮素 B 受体基因 (EDNRB)。我们在 HSCR 患者中发现了 EDNRB 外显子 4 中的 G-->T 错义突变，该突变用 Cys 残基 (W276C) 取代了 G 蛋白偶联受体第五跨膜螺旋中高度保守的 Trp-276 残基。突变的 W276C 受体表现出转染细胞中配体诱导的 Ca2+ 瞬时水平的部分损害。该突变对剂量敏感，W276C 纯合子和杂合子发生 HSCR 的风险分别为 74% 和 21%。对门诺派系患者的基因型分析表明 HSCR 是一种多基因疾病。
Hirschsprung's disease (HSCR) is characterized by an absence of enteric ganglia in the distal colon and a failure of innervation in the gastrointestinal tract. We recently mapped a recessive susceptibility locus (HSCR2) to human chromosome 13q22, which we now demonstrate to be the endothelin-B receptor gene (EDNRB). We identified in HSCR patients a G-->T missense mutation in EDNRB exon 4 that substitutes the highly conserved Trp-276 residue in the fifth transmembrane helix of the G protein-coupled receptor with a Cys residue (W276C). The mutant W276C receptor exhibited a partial impairment of ligand-induced Ca2+ transient levels in transfected cells. The mutation is dosage sensitive, in that W276C homozygotes and heterozygotes have a 74% and a 21% risk, respectively, of developing HSCR. Genotype analysis of patients in a Mennonite pedigree shows HSCR to he a multigenic disorder.