BMPR2 Gene Rearrangements Account for a Significant Proportion of Mutations in Familial and Idiopathic Pulmonary Arterial Hypertension
BMPR2 Gene Rearrangements Account for a Significant Proportion of Mutations in Familial and Idiopathic Pulmonary Arterial Hypertension
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DOI：
10.1002/humu.9398
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发表时间：
2006-02-01
期刊：
影响因子：
3.9
通讯作者：
Trembath, Richard C.
中科院分区：
文献类型：
--
作者：
Aldred, Micheala A.;Vijayakrishnan, Jairam;Trembath, Richard C.
BMPR2 基因突变易患肺动脉高压 (PAH)，这是一种严重的进行性肺血管系统疾病。然而，尽管大多数 PAH 家族与 BMPR2 基因座连锁一致，但测序仅识别出约 55% 的家族病例以及 10% 至 40% 的无家族史（特发性或 IPAH）病例的突变。因此，我们对编码区测序阴性的家族性和特发性 PAH 病例组中较大的基因重排进行了系统分析。使用多重连接依赖性探针扩增对整个基因的外显子剂量进行分析，确定了九种新的重排，并能够在先前报告的缺失的外显子水平上进行全面表征。总体而言，在 58 个家庭中的 7 个和 126 个 IPAH 病例中的 6 个中发现了 BMPR2 重排，这表明大约 12% 的 FPAH 病例和 5% 的 IPAH 病例中存在总重排。重要的是，两个缺失涵盖了所有功能蛋白结构域，预计将导致无效突变，这为疾病易感性的主要分子机制是单倍体不足提供了最有力的支持。剂量分析现在应被视为 PAH 患者分子检查的一部分。 (C) 2006 Wiley-Liss, Inc.
Mutations of the BMPR2 gene predispose to pulmonary arterial hypertension (PAH), a serious, progressive disease of the pulmonary vascular system. However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH). We therefore conducted a systematic analysis for larger gene rearrangements in panels of both familial and idiopathic PAH cases that were negative on sequencing of coding regions. Analysis of exon dosage across the entire gene using Multiplex Ligation-dependent Probe Amplification identified nine novel rearrangements and enabled full characterization at the exon level of previously reported deletions. Overall, BMPR2 rearrangements were identified in 7 of 58 families and 6 of 126 IPAH cases, suggesting that gross rearrangements underlie around 12% of all FPAH cases and 5% of IPAH. Importantly, two deletions encompassed all functional protein domains and are predicted to result in null mutations, providing the strongest support yet that the predominant molecular mechanism for disease predisposition is haploinsufficiency. Dosage analysis should now be considered an integral of part of the molecular work-up of PAH patients. (C) 2006 Wiley-Liss, Inc.