Original research articlePulmonary arterial hypertension (PAH) is a serious disease with a poor prognosis. Possible etiological factors for PAH development include vasospasm, endothelin overactivity, intimal hyperplasia due to increased growth factor secretion, and thrombus formation in small pulmonary arteries.1 The presence of familial disease in ~6% of PAH patients with no obvious secondary causes of PAH suggested that genetic factors play an important role in a substantial proportion of patients with PAH. Linkage analysis and positional cloning have identified mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene in ~60% of familial PAH (FPAH) cases and 10-40% of patients with idiopathic PAH (IPAH).2-4 BMPR2 mutations were also reported in FPAH patients and in 40% of the IPAH cases in a Japanese population, 5 corresponding to the clinical observation that PAH prevalence does not vary among different races. 6 Recent studies have clarified the presence of genome-wide copy-number variations caused by genomic rearrangement such as deletion, duplication, inversion, and translocation of genetic codes spanning more than 1,000 base pairs, with genetic rearrangements of BMPR2 in patients with FPAH resulting in deletion or duplication of one or more exons of the gene. 7,8 Another study identified exonic deletion or duplication in BMPR2 in both FPAH and IPAH cases.9 These findings have demonstrated that BMPR2 mutations may account for a higher proportion of PAH patients than previously expected.Genome-wide analysis of copy-number variations has indicated significant variation in distribution and frequency among populations with different ethnic backgrounds, although such information about the genetic rearrangements of BMPR2 has been limited to the data obtained. Furthermore, deletion break points in exonic deletions of BMPR2 have not been reported. We therefore undertook a thorough genetic analysis of BMPR2 in Japanese patients with PAH and investigated the deletion break points in exonic deletions of BMPR2.
MATERIALS AND METHODS
Study populationThe study included PAH patients and their family members in Kyorin University Hospital, Tokyo, Japan, who were enrolled Purpose: The purpose of this study was to undertake thorough genetic analysis of the bone morphogenetic protein type 2 receptor (BMPR2) gene in patients with pulmonary arterial hypertension.
Methods:We conducted a systematic analysis for larger gene rearrangements together with conventional mutation analysis in 152 pulmonary arterial hypertension patients including 43 patients diagnosed as having idiopathic pulmonary arterial hypertension and 10 diagnosed as having familial pulmonary arterial hypertension.Results: Analysis of the BMPR2 gene revealed each of the four kinds of nonsense and frameshift mutations, one missense mutation, one splice-site mutation, and two types of exonic deletion. For cases in which exons 1-3 were deleted, the 5′ and 3′ break points were located in the AluY repeat sequences in the 5′ side of the adjacent NOP58 gene...
BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. RESULTS: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I 2 infusion, 0% vs 93%, respectively; p < 0.001).
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