Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency
复制标题
DOI：
10.1093/hmg/ddg148
复制
发表时间：
2003-06-01
影响因子：
3.5
通讯作者：
Tomlinson, IPM
中科院分区：
文献类型：
--
作者：
Alam, NA;Rowan, AJ;Tomlinson, IPM
延胡索酸水合酶（FH，延胡索酸酶）基因的种系突变见于隐性FH缺乏综合征以及显性遗传的多发性皮肤和子宫平滑肌瘤病（MCUL）易感性中。我们先前已报道了来自MCUL患者的一些种系FH突变。在本研究中，我们报告了MCUL和FH缺乏患者中的其他FH突变。在约75%的MCUL病例和大多数FH缺乏病例中很容易发现突变。一些更常见的FH突变可能源自奠基者个体。导致蛋白质截断的FH突变在功能上是无效等位基因。与疾病相关的错义FH改变定位于高度保守的残基，主要在酶的活性位点或激活位点内或周围；我们预测这些突变会严重损害酶的功能。FH缺乏和MCUL中的突变谱相似，尽管在后者中突变往往在基因中更靠前的位置发生，并且可能更有可能导致蛋白质截断或缺失。我们发现并非所有FH缺乏患儿的突变携带父母都对平滑肌瘤有强烈的易感性。我们已证实肾癌有时是MCUL的一部分，作为遗传性平滑肌瘤病和肾癌（HLRCC）变异综合征的一部分，并且已表明这些癌症可能具有II型乳头状或集合管形态。我们发现FH突变的类型或位点与MCUL表型的任何方面之间没有关联。对MCUL患者种系中FH功能活性降低的生化检测能够以高灵敏度和特异性指示FH突变的携带者，并且能够在一些没有可检测到的FH突变的患者中检测到FH活性降低。我们得出结论，MCUL可能是一种遗传上同质的肿瘤易感性综合征，主要由延胡索酸酶活性缺失或严重降低导致，目前对平滑肌或肾细胞的功能影响尚不清楚。
Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.