Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer
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DOI：
10.1038/ng849
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发表时间：
2002-04-01
期刊：
影响因子：
30.8
通讯作者：
Aaltonen, LA
中科院分区：
文献类型：
--
作者：
Tomlinson, IPM;Alam, NA;Aaltonen, LA
子宫平滑肌瘤（肌瘤）是常见且临床上重要的肿瘤，但对其病因和发病机制知之甚少(1-3)。我们之前将易患多发性肌瘤、皮肤平滑肌瘤和肾细胞癌的基因定位到染色体 1q42.3-q43（参考文献 4-6）。在这里，我们通过结合绘制关键重组体、鉴定具有种系突变的个体以及筛选已知和预测的转录本，表明该基因编码富马酸水合酶（一种三羧酸循环的酶）。平滑肌瘤病相关突变预计会导致蛋白质缺失或截短，或者高度保守氨基酸的取代或缺失。平滑肌瘤病患者的类淋巴母细胞中富马酸水合酶的活性降低。这种酶在家族性平滑肌瘤中充当肿瘤抑制因子，并且在患有平滑肌瘤病的个体的肿瘤中测得的其活性非常低或不存在。 FH 突变也发生在隐性富马酸水合酶缺乏症 (7-11) 中，患有这种疾病的人的一些父母易患平滑肌瘤。因此，杂合子和纯合子或复合杂合子突变体具有非常不同的临床表型。我们的结果为肌瘤的发病机制提供了线索，并强调了管家蛋白和线粒体蛋白突变在常见类型肿瘤发病机制中的重要性(12-14)。
Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis(1-3). We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency(7-11), and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor(12-14).