De Novo Mutations in the BMPR2 Gene in Patients with Heritable Pulmonary Arterial Hypertension
De Novo Mutations in the BMPR2 Gene in Patients with Heritable Pulmonary Arterial Hypertension
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DOI：
10.1111/ahg.12096
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发表时间：
2015-03-01
影响因子：
1.9
通讯作者：
Gamou, Shinobu
中科院分区：
文献类型：
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作者：
Momose, Yuichi;Aimi, Yuki;Gamou, Shinobu
相当一部分肺动脉高压（PAH）患者的骨形态发生蛋白受体2型（BMPR2）基因存在突变。由于BMPR2突变导致的PAH作为常染色体显性性状遗传，具有几个独特的特征，包括多种突变、降低的遗传率、倾斜的性别比、可变的表达性和遗传预期。为了解决BMPR2突变的这些独特特征的遗传背景，我们对15个PAH家族的BMPR2突变进行了系统分析。采用聚合酶链反应扩增BMPR2基因的外显子编码序列，并对扩增产物进行直接测序，以检测BMPR2基因的点突变。利用多重15位点分析进行亲本鉴定以确认亲本关系。结合家系成员的突变检测和亲本鉴定，我们描述了PAH家系中3例不同模式的BMPR2基因新发突变。这些从头突变可以解释BMPR2中各种各样的突变。与青少年发病相结合，可能存在新发突变和不可传播突变的某种平衡，这使得PAH在一般人群中的频率较低。
A substantial proportion of patients with pulmonary arterial hypertension (PAH) have mutations in the Bone Morphogenetic Protein Receptor type-2 (BMPR2) gene. PAH due to BMPR2 mutations is inherited as an autosomal dominant trait with several unique features, including a wide variety of mutations, reduced penetrance, a skewed gender ratio, variable expressivity and genetic anticipation. To address the genetic background of these unique features of BMPR2 mutation, we conducted a systematic analysis of 15 PAH families with BMPR2 mutation. The exonic protein coding sequence of BMPR2 was amplified by polymerase chain reaction and the products were sequenced directly to detect point mutations in BMPR2. Parental identification was carried out to confirm the parental relationship using multiplex 15 loci analysis. Combining mutation detection in family members with parental identification, we described three cases of de novo mutation in the BMPR2 gene by different modes in a PAH family. These de novo mutations may account for the wide variety of mutations in BMPR2. Taken together with the juvenile onset of the disease, there is possibly some balance of de novo mutations and untransmittable mutations which keeps the frequency of PAH low in the general population.