Bone morphogenetic protein receptor-II mutation Arg491Trp causes malignant phenotype of familial primary pulmonary hypertension

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Abstract

A four-generation pedigree of familial primary pulmonary hypertension (FPPH) with 14 alive members was collected. In the family, three of the 14 alive familial members were diagnosed as FPPH. Mutations in bone morphogenetic protein receptor-II (BMPR-II) gene were screened by using sequencing analysis. A C-to-T transition at position 1471 in exon 11 of the BMPR-II gene was identified, resulting in an Arg491Trp mutation. We confirmed segregation of the mutation within the family and excluded the presence of the mutations in a panel of 240 chromosomes from normal individuals. No mutations were found in BMPR-II gene in other 10 patients with sporadic primary pulmonary hypertension. The Arg491Trp mutation is located in the kinase domain and predicted to disturb the kinase activity of BMPR-II. Total 7 familial members died at age 8–45 years with various symptoms, indicating other genetic or environmental modifiers involved in the modification of the clinical phenotype.

Section snippets

Methods

The investigation protocol was reviewed and approved by the Institutional Review Board of cardiovascular Institute, Chinese Academy of Medical Sciences. All participants were asked to give informed consent. The procedure used in the study was in accordance with the Helsinski Declaration for Human Study in 1997. The patients were ascertained as PPH with the algorithm developed at the National Institute of Health PPH registry [4]. The diagnosis of FPPH was made according to the presence of an

Results

Clinical characterizations for affected members in the FPPH are given in Table 2.

In the four-generation family with FPPH, total 10 members were suspected as FPPH, and 7 died at age 8–45 years (3 men and 4 women), 3 were alive, one male and two females (Fig. 1). The proband was a 37-year-old female who was diagnosed as the disease at age 35 with dyspnea on exertion, hemoptysis, and severe pulmonary arterial hypertension. Electrocardiography showed right axis deviation, P pulmonale, SITIII,

Discussion

The main finding of this study is that in the Chinese FPPH family, the affected member exhibited high penetrance (100%) and malignant clinical phenotype such as acute onset, severe pulmonary hypertension symptoms with hemoptysis, and shorter life.

It has been reported that FPPH families show a pattern of incomplete penetrance in which mostly only 10–20% of family members actually develop overt disease [3]. In this family, all alive affected members had missense mutation Arg491 Trp in exon 11 of

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