Mutations in the Fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America
Mutations in the Fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America
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DOI：
10.1086/376435
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发表时间：
2003-07-01
影响因子：
9.8
通讯作者：
Zbar, B
中科院分区：
文献类型：
--
作者：
Toro, JR;Nickerson, ML;Zbar, B
遗传性平滑肌瘤病和肾细胞癌（HLRCC）是一种常染色体显性遗传疾病，其特征是皮肤和子宫平滑肌肿瘤和/或肾癌。虽然在欧洲家庭中的富马酸水合酶（FH）基因的种系突变的鉴定支持它作为HLRCC的易感基因，其在北美家庭中的作用尚未研究。我们在35个皮肤平滑肌瘤家族中筛选FH的种系突变。31个家系（89%）有FH基因突变。在FH中鉴定了20种不同的突变，其中18种是新的。在这20个突变中，2个是插入，5个是引起移码的小缺失，导致蛋白质的过早截短，13个是错义突变。11个不相关的家庭共享一个共同的突变：R190 H。81人（47名女性和34名男性）有皮肤平滑肌瘤。98%（46/47）的皮肤平滑肌瘤患者同时患有子宫平滑肌瘤。89%（41/46）的皮肤和子宫平滑肌瘤患者行全子宫切除术，其中44%的患者年龄小于或等于30岁。我们确定了13个人在5个家庭与单侧和孤立性肾肿瘤。来自四个家庭的七个人有乳头状II型肾细胞癌，另一个人从这些家庭之一，收集管癌的肾。目前的研究表明FH突变与北美HLRCC相关。HLRCC与临床上显著的子宫肌瘤和侵袭性肾肿瘤相关。本研究还扩展了与HLRCC相关的肾肿瘤和FH突变的组织学谱。
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals ( 47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age less than or equal to 30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.