Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome
Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome
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DOI：
10.1086/430842
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发表时间：
2005-06-01
影响因子：
9.8
通讯作者：
Linehan, WM
中科院分区：
文献类型：
--
作者：
Schmidt, LS;Nickerson, ML;Linehan, WM
Birt-Hogg-Dube综合征（BHD）是一种以毛囊多发性错构瘤（纤维毛囊瘤）为特征的遗传性皮肤病，易使个体发生肾肿瘤和自发性气胸的风险增加。此前，我们通过连锁分析将BHD基因座（也称为FLCN）定位于染色体17 p11.2，随后在我们的筛查小组中的9个BHD家族中的8个先证者中发现了一个新基因的种系突变。受影响的五个家庭的成员继承了插入/缺失的胞嘧啶在C-8道外显子11。在52个BHD家族中的22个家系的先证者中，通过外显子11筛查也发现了这种突变，因此代表了BHD突变的高变“热点”。在这里，我们通过直接序列分析从这个大的BHD队列中筛选了剩余的30个家族，并在我们研究招募的所有BHD家族中鉴定了84%（51/61）的生殖系BHD突变。突变位于沿着整个长度的编码区，包括16个插入/缺失，3个无义，和3个剪接位点突变。大多数BHD突变被预测为截短BHD蛋白，卵泡素。在外显子11热点突变的患者中，观察到C缺失患者的肾肿瘤明显少于C插入突变患者。然而，在两个BHD大家族的先证者中没有发现编码序列突变，这些家族的BHD受影响成员共享其家族的BHD受影响单倍型。在53个BHD家族中，其成员遗传了生殖系突变或受影响的单倍型，24个（45%）至少有一个成员患有肾肿瘤。三个家族性肾嗜酸细胞瘤被确定为BHD突变，这是第一个与这种罕见形式的肾脏肿瘤相关的疾病基因。本研究扩展了BHD突变谱，并评估了BHD家族中基因型-表型相关性。
Birt-Hogg-Dube syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C-8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.