BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension

Aldred, Micheala A.; Vijayakrishnan, Jairam; James, Victoria; Soubrier, Florent; Gómez-Sánchez, Miguel Ángel; Mårtensson, G; Galiè, Nazzareno; Manes, Alessandra; Corris, Paul A.; Simonneau, Gérald; Humbert, Marc; Morrell, Nicholas W.; Trembath, Richard C.

doi:10.1002/humu.9398

Cited by 200 publications

(158 citation statements)

References 20 publications

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“…The exonic deletion of exon 10 was also reported previously, 9 although it is not clear whether their deletions are identical to those in our results, because break points were not reported in the previous study.…”

Section: Discussionsupporting

confidence: 78%

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Kataoka

Aimi

Yanagisawa

et al. 2013

Genetics in Medicine

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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...

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Section: Discussionsupporting

confidence: 78%

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Kataoka

Aimi

Yanagisawa

et al. 2013

Genetics in Medicine

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“…Mutations have been detected in up to 70% of recognized familial PAH cases Morisaki et al, 2004] ( Aldred et al, 2006), whereas in IPAH the reported mutation detection rate ranges from 11% to 40% [Thomson et al, [Cogan et al, 2005] ( Aldred et al, 2006).…”

Section: Spectrum Of Bmpr2 Mutations In Pahmentioning

confidence: 99%

“…Whenever possible segregation of mutant alleles was determined within families, and the presence of the mutations was excluded from a panel of up to 300 normal chromosomes. At a single center (University of Leicester), screening for gene rearrangements was performed using multiplex ligation-dependent probe amplification (MLPA) technology (Aldred et al, 2006). The mutation nomenclature follows current guidelines as recommended by the Human Genome Variation Society (www.hgvs.org/mutnomen/) ( Table 1).…”

Section: Spectrum Of Bmpr2 Mutations In Pahmentioning

confidence: 99%

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Mutations of the TGF-β type II receptorBMPR2 in pulmonary arterial hypertension

et al. 2006

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Communicated by Maria Rita Passos-BuenoPulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-b cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age-and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the

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“…Interestingly, PVOD can appear in a familial context and some patients with a definite diagnosis of PVOD have been reported to carry a BMPR2 mutation. These observations suggest the existence of a genetic risk factor in the development of PVOD [8,[42][43][44][45][46]. The involvement of a genetic pattern in the development of PVOD emphasizes once more the similarities between PVOD and PAH.…”

mentioning

confidence: 99%

Pulmonary veno-occlusive disease: advances in clinical management and treatments

Huertas

Girerd

Dorfmüller

et al. 2011

Expert Review of Respiratory Medicine

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BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension

Cited by 200 publications

References 20 publications

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Mutations of the TGF-β type II receptorBMPR2 in pulmonary arterial hypertension

Pulmonary veno-occlusive disease: advances in clinical management and treatments

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