HGNC Approved Gene Symbol: BMPR2
Cytogenetic location: 2q33.1-q33.2 Genomic coordinates (GRCh38): 2:202,376,327-202,567,749 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1-q33.2 | Pulmonary hypertension, familial primary, 1, with or without HHT | 178600 | Autosomal dominant | 3 |
| Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated | 178600 | Autosomal dominant | 3 | |
| Pulmonary venoocclusive disease 1 | 265450 | Autosomal dominant | 3 |
Bone morphogenetic proteins (BMPs) are a family of proteins that induce bone formation at extracellular sites in vivo. BMPs act on osteoblasts and chondrocytes as well as other cell types, including neurocells, and they play important roles in embryonal development. Members of the BMP family include BMP1 (112264) to BMP6 (112266), BMP7 (112267), also called osteogenic protein-1 (OP1), OP2 (BMP8; 602284), and others. BMPs belong to the transforming growth factor beta (TGF-beta) superfamily, which includes, in addition to the TGF-betas (e.g., 190180), activin/inhibins (e.g., alpha-inhibin; 147380), mullerian inhibiting substance (600957), and glial cell line-derived neurotrophic factor (600837). TGF-betas and activins transduce their signals through the formation of heteromeric complexes of 2 different types of serine (threonine) kinase receptors: type I receptors of about 50 to 55 kD and type II receptors of about 70 to 80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. BMPR2 is a type II receptor for BMPs.
Rosenzweig et al. (1995) reported the cDNA cloning and characterization of a human type II receptor for BMPs, which they called BMPR II, that is distantly related to DAF4, a BMP type II receptor in Caenorhabditis elegans.
By analysis of a monochromosome hybrid mapping panel and by FISH, Astrom et al. (1999) mapped the BMPR2 gene to chromosome 2q33-q34.
Rosenzweig et al. (1995) showed that, in transfected COS-1 cells, BMP7 and, less efficiently, BMP4 (112262) bound to BMPR II. BMPR II bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type I receptors for BMPs. A transcriptional activation signal was transduced by BMPR II in the presence of type I receptors after stimulation by BMP7.
In an investigation of the molecular bases of common nonfamilial forms of pulmonary hypertension, Du et al. (2003) evaluated the pattern of expression of several genes in lung biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The genes included angiopoietin-1 (ANGPT1; 601667), a protein involved in the recruitment of smooth muscle cells around blood vessels; TIE2 (600221), the endothelial-specific receptor for angiopoietin-1; bone morphogenetic protein receptor 1A (BMPR1A; 601299); and BMPR2. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. The expression of angiopoietin-1 mRNA and the protein itself and the phosphorylation of TIE2 were strongly upregulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. The findings suggested that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2, and consequently identified specific molecular targets for therapeutic intervention.
Machado et al. (2003) determined that TCTEL1 (601554), a light chain of the motor complex dynein, interacted with the cytoplasmic domain of BMPR2 and was also phosphorylated by BMPR2, a function disrupted by primary pulmonary hypertension (PPH1; 178600)-causing mutations within exon 12 (e.g., 600799.0002). BMPR2 and TCTEL1 colocalized to endothelium and smooth muscle within the media of pulmonary arterioles, key sites of vascular remodeling in PPH. The authors proposed that loss of interaction and lack of phosphorylation of TCTEL1 by BMPR2 may contribute to the pathogenesis of PPH.
Using RT-PCR, immunofluorescence, and flow cytometric analyses, Cejalvo et al. (2007) demonstrated that human thymus and cortical epithelial cells produced BMP2 (112261) and BMP4 and that both thymocytes and thymic epithelium expressed the molecular machinery to respond to these proteins. The receptors BMPR1A and BMPR2 were mainly expressed by cortical thymocytes, whereas BMPR1B (603248) was expressed in the majority of thymocytes. BMP4 treatment of chimeric human-mouse fetal thymic organ cultures seeded with CD34 (142230)-positive human thymic progenitors resulted in reduced cell recovery and inhibition of differentiation of CD4 (186940)/CD8 (see 186910) double-negative to double-positive stages. Cejalvo et al. (2007) concluded that BMP2 and BMP4 have a role in human T-cell differentiation.
Tsang et al. (2009) showed that mammalian NIPA1 (608145) is an inhibitor of BMP signaling. NIPA1 physically interacted with the BMPR2, and this interaction did not require the cytoplasmic tail of BMPR2. The mechanism by which NIPA1 inhibited BMP signaling involved downregulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 altered the trafficking of BMPR2 and were less efficient at promoting BMPR2 degradation than wildtype NIPA1. In addition, 2 other members of the endosomal group of hereditary spastic paraplegia (HSP) proteins, spastin (SPAST; 604277) and spartin (SPG20; 607111), inhibited BMP signaling. Since BMP signaling is important for distal axonal function, Tsang et al. (2009) proposed that dysregulation of BMP signaling could be a unifying pathologic component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.
Davis et al. (2008) demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in expression of mature miR21 through a posttranscriptional step, promoting the processing of primary transcripts of miR21 (pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (608828). TGF-beta and BMP-specific SMAD signal transducers SMAD1 (601595), SMAD2 (601366), SMAD3 (603109), and SMAD5 (603110) are recruited to pri-miR21 in a complex with the RNA helicase p68 (DDX5; 180630), a component of the Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not required for this process. Davis et al. (2008) concluded that regulation of microRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signaling pathways.
In a follow-up to the report of Davis et al. (2008), Drake et al. (2011) found that BMPR2 was essential for the SMAD-mediated miR processing. Loss of SMAD9 (603295) also affected miR processing in smooth muscle cells and in endothelial cells, but it did not affect canonical BMP signaling. Knockdown of individual receptor SMADs 1, 5, and 9 decreased levels of processed miR21 levels in both types of cells, suggesting that the miR processing pathway forms a complex.
Sawada et al. (2014) used TNF (191160) to stimulate pulmonary artery endothelial cells expressing reduced BMPR2 due to treatment with small interfering RNA (siRNA). The authors observed enhanced GMCSF (CSF2; 138960) production, with little effect on GMCSF mRNA expression, compared with treatment with control siRNA. More modest effects were observed with IL6 (147620) and IL8 (146930) production. The effect of reduced BMPR2 expression and increased GMCSF translation was dependent on sustained activation of p38 (MAPK14; 600289) and impairment of stress granule assembly. Immunoblot and immunohistochemical analysis of idiopathic pulmonary arterial hypertension (PAH) lungs showed increased GMCSF and TNF, as well as GMCSFR (CSF2RA; 306250) expression in endothelia, thickened intima, and hypertrophied media. Administration of Gmcsf to mice exposed to hypoxia, but not to control mice, exacerbated PAH and could be prevented by Gmcsf blockade. Sawada et al. (2014) concluded that reduced BMPR2 subverts the stress granule response, heightens GMCSF mRNA translation, increases inflammatory cell recruitment, and exacerbates pulmonary arterial hypertension.
Primary Pulmonary Hypertension 1 and/or Pulmonary Venooclusive Disease 1
The International PPH Consortium et al. (2000) and Deng et al. (2000) reported that mutations in the BMPR2 gene can cause primary pulmonary hypertension (PPH), a locus for which resides on chromosome 2q33 (PPH1; 178600). BMPR2 mutations were found in 7 of 8 of the PPH1 families exhibiting linkage to markers adjacent to BMPR2 by the International PPH Consortium et al. (2000) and in 9 of 19 of the families exhibiting linkage and/or haplotype sharing with markers adjacent to BMPR2 by Deng et al. (2000). Both groups reported heterogeneous BMPR2 mutations that included termination, frameshift, and nonconservative missense changes in amino acid sequence.
Thomson et al. (2000) analyzed the BMPR2 gene in 50 unrelated patients with apparent sporadic PPH and identified 11 different heterozygous mutations in 13 of the 50 PPH patients, including 3 missense, 3 nonsense (see, e.g., 600799.0019), and 5 frameshift mutations. Analysis of parental DNA was possible in 5 cases and showed 3 occurrences of paternal transmission and 2 of de novo mutation of the BMPR2 gene. Thomson et al. (2000) noted that because of low penetrance, in the absence of detailed genealogic data, familial cases may be overlooked.
Machado et al. (2001) reported the molecular spectrum of BMPR2 mutations in 47 families with PPH and in 3 patients with sporadic PPH. In the cohort of patients, they identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations were predicted to lead to a premature termination codon. In vitro expression analysis demonstrated loss of BMPR2 function for a number of the identified mutations. These data suggested that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. The observed overall range for the age at onset of symptoms of PPH was 1 to 60 years. In 1 family, the age at onset for the 8 affected individuals ranged from 14 to 60 years. The authors interpreted these observations as indicating that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.
Most patients with primary pulmonary hypertension are thought to have sporadic, not inherited, disease. Because clinical disease develops in only 10 to 20% of persons carrying the gene for familial primary pulmonary hypertension, Newman et al. (2001) hypothesized that many patients with apparently sporadic primary pulmonary hypertension may actually have familial primary pulmonary hypertension. Over a period of 20 years, they developed a registry of 67 families affected by familial primary pulmonary hypertension. They discovered shared ancestry among 5 subfamilies, including 394 known members spanning several generations, which were traced back to a founding couple in the mid-1800s. PPH had been diagnosed in 18 family members, 12 of whom were first thought to have sporadic disease. In 7 of the 18, the initial misdiagnosis was another form of cardiopulmonary disease. The cys118-to-trp mutation (600799.0005) was found in 6 members affected by PPH and in 6 individuals who were from the pedigree recognized as being carriers.
To determine the mechanism of altered BMPR2 function in primary pulmonary hypertension, Rudarakanchana et al. (2002) transiently transfected pulmonary vascular smooth muscle cells with mutant BMPR2 constructs and fusion proteins. Substitution of cysteine residues in the ligand binding (i.e., 600799.0005, 600799.0016) or kinase (600799.0006) domain prevented trafficking of BMPR2 to the cell surface, and reduced binding of radiolabeled BMP4. In addition, transfection of cysteine-substituted BMPR2 markedly reduced basal and BMP4-stimulated transcriptional activity of a BMP/SMAD-responsive luciferase reporter gene (3GC2wt-Lux), compared with wildtype BMPR2, suggesting a dominant-negative effect of these mutants on SMAD signaling. In contrast, BMPR2 containing noncysteine substitutions in the kinase domain (600799.0007, 600799.0008, 600799.0013) were localized to the cell membrane, although these also suppressed the activity of 3GC2wt-Lux. Interestingly, BMPR2 mutations within the cytoplasmic tail (600799.0002) trafficked to the cell surface, but retained the ability to activate 3GC2wt-Lux. Transfection of mutant, but not wildtype, constructs into a mouse epithelial cell line led to activation of p38 MAPK (MAPK14; 600289) and increased serum-induced proliferation compared with the wildtype receptor, which was partly p38 MAPK-dependent. The authors concluded that mutations in BMPR2 heterogeneously inhibit BMP/SMAD-mediated signaling by diverse molecular mechanisms. However, all mutants studied demonstrate a gain of function involving upregulation of p38 MAPK-dependent pro-proliferative pathways.
Humbert et al. (2002) analyzed the BMPR2 gene in 33 unrelated patients with sporadic PPH and 2 sisters with PPH, all of whom had taken fenfluramine derivatives. Three BMPR2 mutations (see, e.g., 600799.0020) were identified in 3 (9%) of the 33 unrelated patients, and a fourth mutation (R211X; 600799.0019) was identified in the 2 sisters. The latter mutation, as well as 1 of the sporadic mutations, had previously been identified in patients with PPH unassociated with fenfluramine derivatives.
In a family in which the proband had pulmonary venoocclusive disease (PVOD1; 265450) and her mother had pulmonary hypertension, Runo et al. (2003) analyzed the BMPR2 gene and identified heterozygosity for a 1-bp deletion (600799.0021) in the proband and her unaffected sister. DNA was not available from their mother, who had known pulmonary hypertension and died of right heart failure, or from the maternal grandparents.
In a patient with pulmonary arterial hypertension and PVOD, Machado et al. (2006) identified heterozygosity for a nonsense mutation (600799.0022) the BMPR2 gene.
In 25 families with PPH and 106 patients with sporadic PPH, all of whom were negative for mutations in the BMPR2 gene by DHPLC analysis or direct sequencing, Aldred et al. (2006) performed multiplex ligation-dependent probe amplification (MLPA) analysis to detect gross BMPR2 rearrangements. Ten different deletions were identified in 7 families and 6 sporadic cases (see, e.g., 600799.0023-600799.0025). One patient with familial PPH had histologic features of pulmonary venoocclusive disease and was found to have a deletion of exon 2 of the BMPR2 gene (600799.0023); the exon 2 deletion was also identified in an unrelated family with PPH and no known evidence of PVOD. Aldred et al. (2006) noted that 2 large deletions were predicted to result in null alleles (see 600799.0025), providing support for the hypothesis that the predominant molecular mechanism for disease predisposition is haploinsufficiency.
Phillips et al. (2008) studied SNP genotypes of TGF-beta (190180) in BMPR2 mutation carriers with pulmonary hypertension and examined the age of diagnosis and penetrance of the pulmonary hypertension phenotype. BMPR2 heterozygotes with least active -509 or codon 10 TGFB1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years, respectively), than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis showed that those with less active SNPs had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay (NMD)-resistant BMPR2 mutations and the least, intermediate, and most active -509 TGFB1 SNP phenotypes had penetrances of 33%, 72%, and 80%, respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active SNP alleles had penetrances of 33%, 72%, and 75% (P = 0.005). Phillips et al. (2008) concluded that the TGFB1 SNPs studied modulate age at diagnosis and penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFB/BMP signaling imbalance. The authors considered this modulation an example of synergistic heterozygosity.
Using enzymatic and fluorescence activity-based techniques, Nasim et al. (2008) demonstrated that PPH-causing nonsense and frameshift BMPR2 mutations (see, e.g., 600799.0002) trigger NMD, providing further evidence that haploinsufficiency is a major molecular consequence of disease-related BMPR2 mutations. Missense mutations (see, e.g., 600799.0006, 600799.0007, and 600799.0013) resulted in heterogeneous functional defects in BMPR2 activity, including impaired phosphorylation of the type 1 receptors BMPR1A and BMPR1B (603248), reduced receptor-receptor interactions, and altered receptor complex stoichiometry leading to perturbation of downstream signaling pathways. Nasim et al. (2008) concluded that the intracellular domain of BMPR2 is both necessary and sufficient for receptor complex interaction, and suggested that stoichiometric imbalance, due to either haploinsufficiency or loss of optimal receptor-receptor interactions, impairs BMPR2-mediated signaling in PPH.
In a cohort of 48 patients with pulmonary arterial hypertension (PAH), 24 of whom had histologic evidence of PVOD, Montani et al. (2008) identified mutations in the BMPR2 gene in 2 patients with PVOD (600799.0027 and 600799.0028) and in 4 patients with no evidence of PVOD.
In pulmonary endothelial cells derived from 2 of 3 PPH1 patients with BMPR2 mutations, Drake et al. (2011) found loss of miR21 induction in response to BMP9. These cells also showed greater proliferation compared to controls; overexpression of miR21 induced growth suppression. However, canonical BMP signaling was only mildly attenuated in these cells. The findings suggested that disruption of the noncanonical BMP-mediated pathway resulting in aberrant miR processing may play an important role in the pathogenesis of PPH.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported deletion of a T in an ATT repeat (2579delT) in exon 12 of the BMPR2 gene. This frameshift mutation was predicted to result in premature termination after 10 amino acid residues. The resulting truncation includes the large cytoplasmic domain of the 1,038-amino acid BMPR2 protein. The authors concluded that this mutation is likely to impede heteromeric receptor complex formation at the cell surface, a requirement for normal signal transduction. They also concluded that the mechanism of PPH1 causation may be either haploinsufficiency or a dominant-negative mechanism. In a family with primary pulmonary hypertension, Deng et al. (2000) independently identified the 2579delT mutation.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported a nonsense mutation in exon 12 of the BMPR2 gene, an arg899-to-ter (R899X) substitution that was caused by a C-to-T transition at base 2695. This termination mutation was predicted to truncate the large cytoplasmic domain of the 1,038-amino acid BMPR2 protein. The authors concluded that this mutation is likely to impede heteromeric receptor complex formation at the cell surface.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported a nonsense mutation in exon 2 of the BMPR2 gene, ser73-to ter (S73X), that was caused by a C-to-G transversion at base 218. This termination mutation was predicted to truncate the protein before the transmembrane domain; if translated, the protein may fail to reach the cell surface.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported a deletion of an A in exon 3 of the BMPR2 gene at position 355. This frameshift mutation was predicted to result in a premature termination that would truncate the protein before the transmembrane domain; if translated, the protein may fail to reach the cell surface.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported a T-to-G transversion at position 354 of the BMPR2 gene resulting in a cys118-to-trp (C118W) substitution. This amino acid substitution, which occurs at a highly conserved and functionally important site of the BMPR2 protein, was predicted to perturb ligand binding.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported a G-to-A transition at position 1042 in exon 8 of the BMPR2 gene resulting in a cys347-to-tyr (C347Y) substitution. This amino acid substitution occurs at a highly conserved and functionally important site of the BMPR2 protein.
In a family with primary pulmonary hypertension (PPH1; 178600), the International PPH Consortium et al. (2000) reported an A-to-G transition at position 1454 in exon 11 of the BMPR2 gene that was predicted to result in an asp485-to-gly (D485G) substitution. This amino acid substitution occurs at a highly conserved and functionally important site of the BMPR2 protein.
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a C-to-T transition at position 1471 in exon 11 of the BMPR2 gene that was predicted to result in an arg491-to-trp (R491W) substitution. This amino acid substitution occurs at an arginine that is highly conserved in all type II TGF-beta receptors and appears to be homologous to the invariant arg280 in subdomain XI in other protein kinases (Hanks et al., 1988).
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a GGGGA deletion at position 1099-1103 in exon 8 of the BMPR2 gene that results in a frameshift and premature termination of the BMPR2 protein following codon 368.
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a 4-bp deletion (CTTT) and 3-bp insertion (AAA) at position 507-510 in exon 4 of the BMPR2 gene that results in premature termination of the BMPR2 protein, changing cysteine-169 to ter (C169X).
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a C-to-T transition at position 2617 in exon 12 of the BMPR2 gene that was predicted to result in an arg873-to-ter mutation (R873X).
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a G-to-A transition at position 1472 in exon 11 of the BMPR2 gene that was predicted to result in an arg491-to-gln mutation (R491Q). This amino acid substitution occurs at an arginine that is highly conserved in all type II TGF-beta receptors and appears to be homologous to arg280 in subdomain XI in other protein kinases (Hanks et al., 1988).
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a 2-bp deletion (AG) and 1-bp insertion (T) at position 690-691 in exon 6 of the BMPR2 gene that results in a frameshift leading to premature termination of the BMPR2 protein 21 amino acid residues following codon 230.
In 2 affected members of the same generation of a family with primary pulmonary hypertension (PPH1; 178600), Machado et al. (2001) identified a T-to-C transition at nucleotide 367 of the BMPR2 gene, predicted to result in a cys123-to-arg substitution. The ages of onset were 9 and 26 years.
In 5 affected members of 2 generations of a family with primary pulmonary hypertension (PPH1; 178600), Machado et al. (2001) identified a T-to-A transversion at nucleotide 367 of the BMPR2 gene, predicted to result in a cys123-to-ser substitution.
In 2 apparently unrelated families, Machado et al. (2001) found that multiple members affected by primary pulmonary hypertension (PPH1; 178600) carried a C-to-T transition at nucleotide 994 of the BMPR2 gene, resulting in an arg332-to-ter mutation. In one family, a parent and child were affected, with onset at 28 and 32 years of age; in the other family, 8 members of 3 generations were affected with an age of onset ranging from 13 to 42 years.
In a Finnish patient with primary pulmonary hypertension (PPH1; 178600), Sankelo et al. (2005) identified a heterozygous 2696G-C transversion in exon 12 of the BMPR2 gene, resulting in an arg899-to-pro (R899P) substitution in the C-terminal cytoplasmic domain. Functional expression studies showed that the R899P mutation resulted in constitutive activation of MAPK14 (600289). A nonsense mutation at the same codon (R899X; 600799.0002) had previously been reported.
In a patient with sporadic primary pulmonary hypertension (PPH1; 178600), Thomson et al. (2000) identified heterozygosity for a 631C-T transition in exon 6 of the BMPR2 gene, resulting in an arg211-to-ter (R211X) substitution. The mutation was not found in 150 normal chromosomes.
Machado et al. (2001) found the R211X mutation in 2 affected members of the same generation of an Italian family with primary pulmonary hypertension. Age of onset of disease was 17 and 18 years, respectively.
Humbert et al. (2002) analyzed the BMPR2 gene in 2 sisters who developed pulmonary arterial hypertension after 1 and 2 months' exposure to dexfenfluramine, respectively, and identified the R211X mutation in both sisters. The mutation was not found in 260 ethnically matched control chromosomes.
In a patient who developed pulmonary arterial hypertension (PPH1; 178600) after taking fenfluramine for 2 months, Humbert et al. (2002) identified a 545G-A transition in exon 5 of the BMPR2 gene, resulting in a gly182-to-asp (G182D) substitution in the kinase domain of the protein.
In 2 affected members from 2 generations of a family with primary pulmonary hypertension (PPH1; 178600), Machado et al. (2001) identified heterozygosity for a 1-bp deletion in exon 1 of the BMPR2 gene (44delC), predicted to cause premature termination of the protein 30 codons downstream. Age at onset of disease was 36 and 38 years, respectively.
In a woman who presented with pulmonary venoocclusive disease (PVOD1; 265450) at age 36, Runo et al. (2003) identified heterozygosity for the 44delC mutation in the BMPR2 gene. The patient's deceased mother was known to have had pulmonary hypertension and died of complications of right heart failure; because lung biopsy and autopsy were not performed, it was unknown whether the mother's pulmonary hypertension was from PPH or PVOD.
In a patient with pulmonary arterial hypertension and pulmonary venoocclusive disease (265450), Machado et al. (2006) identified heterozygosity for a 120T-G transversion in exon 2 of the BMPR2 gene, resulting in a tyr40-to-ter (Y40X) substitution.
In the probands of 2 families with primary pulmonary hypertension (PPH1; 178600), Aldred et al. (2006) identified heterozygosity for deletion of exon 2 of the BMPR2 gene, predicted to result in loss of 57 amino acids from the extracellular ligand-binding domain. The affected relatives, 1 in the first family and 3 in the second, were all deceased. The proband of the second family had histologic features of pulmonary venoocclusive disease (PVOD1; 265450).
In 2 sibs and an unrelated pediatric patient with primary pulmonary hypertension (PPH1; 178600), Aldred et al. (2006) identified heterozygosity for deletion of exon 10 of the BMPR2 gene, resulting in loss of 45 amino acids from the kinase domain. The deletion was predicted to cause a frameshift and premature termination of exon 11 that was expected to result in nonsense-mediated decay (NMD). The sibs inherited the mutation from their unaffected father; in the other case, the mutation was inherited from the unaffected mother.
In a patient with primary pulmonary hypertension (PPH1; 178600), Aldred et al. (2006) identified heterozygosity for a deletion of exons 1 through 13 in the BMPR2 gene, confirmed to extend into the 5-prime untranslated region and predicted to result in a complete null allele. The mutation was not found in either parent.
In a woman with primary pulmonary hypertension (PPH1; 178600) diagnosed at age 24 years, Rigelsky et al. (2008) identified a heterozygous 1297C-T transition in exon 10 of the BMPR2 gene, resulting in a gln433-to-ter (Q433X) substitution. She developed massive hemoptysis at age 35, prompting the discovery of multiple pulmonary arteriovenous malformations consistent with a diagnosis of hereditary hemorrhagic telangiectasia (HHT). She also had recurrent epistaxis and nasal telangiectasia. The patient was adopted, and there was no family history available. Rigelsky et al. (2008) noted that, although PAH with HHT had usually only been associated with mutations in the ACVRL1 gene (601284), their patient was the first report of PAH and HHT associated with a mutation in the BMPR2 gene. The findings indicated a common molecular pathogenesis in PAH and HHT, most likely dysregulated BMP9 (GDF2; 605120) signaling.
Montani et al. (2008) reported a patient with pulmonary arterial hypertension who had histologic evidence of pulmonary venoocclusive disease (PVOD1; 265450) and a heterozygous 604A-T transversion in exon 5 of the BMPR2 gene, resulting in an asn202-to-tyr (N202Y) substitution.
Montani et al. (2008) reported a patient with pulmonary arterial hypertension who had histologic evidence of pulmonary venoocclusive disease (PVOD1; 265450) and a heterozygous 583G-T transversion in exon 5 of the BMPR2 gene, resulting in a glu195-to-ter (E195X) substitution.
Aldred, M. A., Vijayakrishnan, J., James, V., Soubrier, F., Gomez-Sanchez, M. A., Martensson, G., Galie, N., Manes, A., Corris, P., Simonneau, G., Humbert, M., Morrell, N. W., Trembath, R. C. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. (Abstract) Hum. Mutat. 27: 212-213, 2006. Note: Full article online. [PubMed: 16429403] [Full Text: https://doi.org/10.1002/humu.9398]
Astrom, A.-K., Jin, D., Imamura, T., Roijer, E., Rosenzweig, B., Miyazono, K., ten Dijke, P., Stenman, G. Chromosomal localization of three human genes encoding bone morphogenetic protein receptors. Mammalian Genome 10: 299-302, 1999. [PubMed: 10051328] [Full Text: https://doi.org/10.1007/s003359900990]
Cejalvo, T., Sacedon, R., Hernandez-Lopez, C., Diez, B., Gutierrez-Frias, C., Valencia, J., Zapata, A. G., Varas, A., Vicente, A. Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development. Immunology 121: 94-104, 2007. [PubMed: 17425602] [Full Text: https://doi.org/10.1111/j.1365-2567.2007.02541.x]
Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454: 56-61, 2008. [PubMed: 18548003] [Full Text: https://doi.org/10.1038/nature07086]
Deng, Z., Morse, J. H., Slager, S. L., Cuervo, N., Moore, K. J., Venetos, G., Kalachikov, S., Cayanis, E., Fischer, S. G., Barst, R. J., Hodge, S. E., Knowles, J. A. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67: 737-744, 2000. [PubMed: 10903931] [Full Text: https://doi.org/10.1086/303059]
Drake, K. M., Zygmunt, D., Mavrakis, L., Harbor, P., Wang, L., Comhair, S. A., Erzurum, S. C., Aldred, M. A. Altered microRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am. J. Resp. Crit. Care Med. 184: 1400-1408, 2011. [PubMed: 21920918] [Full Text: https://doi.org/10.1164/rccm.201106-1130OC]
Du, L., Sullivan, C. C., Chu, D., Cho, A. J., Kido, M., Wolf, P. L., Yuan, J. X.-J., Deutsch, R., Jamieson, S. W., Thistlethwaite, P. A. Signaling molecules in nonfamilial pulmonary hypertension. New Eng. J. Med. 348: 500-509, 2003. [PubMed: 12571257] [Full Text: https://doi.org/10.1056/NEJMoa021650]
Hanks, S. K., Quinn, A. M., Hunter, T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241: 42-52, 1988. [PubMed: 3291115] [Full Text: https://doi.org/10.1126/science.3291115]
Humbert, M., Deng, Z., Simonneau, G., Barst, R. J., Sitbon, O., Wolf, M., Cuervo, N., Moore, K. J., Hodge, S. E., Knowles, J. A., Morse, J. H. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Europ. Resp. J. 20: 518-523, 2002. [PubMed: 12358323] [Full Text: https://doi.org/10.1183/09031936.02.01762002]
International PPH Consortium, Lane, K. B., Machado, R. D., Pauciulo, M. W., Thomson, J. R., Phillips, J. A., III, Loyd, J. E., Nichols, W. C., Trembath, R. C. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nature Genet. 26: 81-84, 2000. [PubMed: 10973254] [Full Text: https://doi.org/10.1038/79226]
Machado, R. D., Aldred, M. A., James, V., Harrison, R. E., Patel, B., Schwalbe, E. C., Gruenig, E., Janssen, B., Koehler, R., Seeger, W., Eickelberg, O., Olschewski, H., and 21 others. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum. Mutat. 27: 121-132, 2006. [PubMed: 16429395] [Full Text: https://doi.org/10.1002/humu.20285]
Machado, R. D., Pauciulo, M. W., Thomson, J. R., Lane, K. B., Morgan, N. V., Wheeler, L., Phillips, J. A., III, Newman, J., Williams, D., Galie, N., Manes, A., McNeil, K., and 11 others. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 68: 92-102, 2001. [PubMed: 11115378] [Full Text: https://doi.org/10.1086/316947]
Machado, R. D., Rudarakanchana, N., Atkinson, C., Flanagan, J. A., Harrison, R., Morrell, N. W., Trembath, R. C. Functional interaction between BMPR-II and Tctex-1, a light chain of dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Hum. Molec. Genet. 12: 3277-3286, 2003. [PubMed: 14583445] [Full Text: https://doi.org/10.1093/hmg/ddg365]
Montani, D., Achouh, L., Dorfmuller, P., Le Pavec, J., Sztrymf, B., Tcherakian, C., Rabiller, A., Haque, R., Sitbon, O., Jais, X., Dartevelle, P., Maitre, S., Capron, F., Musset, D., Simonneau, G., Humbert, M. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine 87: 220-233, 2008. [PubMed: 18626305] [Full Text: https://doi.org/10.1097/MD.0b013e31818193bb]
Nasim, M. T., Ghouri, A., Patel, B., James, V., Rudarakanchana, N., Morrell, N. W., Trembath, R. C. Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum. Molec. Genet. 17: 1683-1694, 2008. [PubMed: 18321866] [Full Text: https://doi.org/10.1093/hmg/ddn059]
Newman, J. H., Wheeler, L., Lane, K. B., Loyd, E., Gaddipati, R., Phillips, J. A., III, Loyd, J. E. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. New Eng. J. Med. 345: 319-324, 2001. Note: Erratum: New Eng. J. Med. 345: 1506 only, 2001. Erratum: New Eng. J. Med. 346: 1258 only, 2002. [PubMed: 11484688] [Full Text: https://doi.org/10.1056/NEJM200108023450502]
Phillips, J. A., III, Poling, J. S., Phillips, C. A., Stanton, K. C., Austin, E. D., Cogan, J. D., Wheeler, L., Yu, C., Newman, J. H., Dietz, H. C., Loyd, J. E. Synergistic heterozygosity for TGF-beta-1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet. Med. 10: 359-365, 2008. [PubMed: 18496036] [Full Text: https://doi.org/10.1097/GIM.0b013e318172dcdf]
Rigelsky, C. M., Jennings, C., Lehtonen, R., Minai, O. A., Eng, C., Aldred, M. A. BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. Am. J. Med. Genet. 146A: 2551-2556, 2008. [PubMed: 18792970] [Full Text: https://doi.org/10.1002/ajmg.a.32468]
Rosenzweig, B. L., Imamura, T., Okadome, T., Cox, G. N., Yamashita, H., ten Dijke, P., Heldin, C.-H., Miyazono, K. Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc. Nat. Acad. Sci. 92: 7632-7636, 1995. [PubMed: 7644468] [Full Text: https://doi.org/10.1073/pnas.92.17.7632]
Rudarakanchana, N., Flanagan, J., Chen, H., Upton, P. D., Machado, R., Patel, D., Trembath, R. C., Morrell, N. W. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum. Molec. Genet. 11: 1517-1525, 2002. [PubMed: 12045205] [Full Text: https://doi.org/10.1093/hmg/11.13.1517]
Runo, J. R., Vnencak-Jones, C. L., Prince, M., Loyd, J. E., Wheeler, L., Robbins, I. M., Lane, K. B., Newman, J. H., Johnson, J., Nichols, W. C., Phillips, J. A., III. Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am. J. Resp. Crit. Care Med. 167: 889-894, 2003. [PubMed: 12446270] [Full Text: https://doi.org/10.1164/rccm.200208-861OC]
Sankelo, M., Flanagan, J. A., Machado, R., Harrison, R., Rudarakanchana, N., Morrell, N., Dixon, M., Halme, M., Puolijoki, H., Kere, J., Elomaa, O., Kupari, M., Raisanen-Sokolowski, A., Trembath, R. C., Laitinen, T. BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum. Mutat. 26: 119-124, 2005. [PubMed: 15965979] [Full Text: https://doi.org/10.1002/humu.20200]
Sawada, H., Saito, T., Nickel, N. P., Alastalo, T.-P., Glotzbach, J. P., Chan, R., Haghighat, L., Fuchs, G., Januszyk, M., Cao, A., Lai, Y.-J., Perez, V. de J., Kim, Y.-M., Wang, L., Chen, P.-I., Spiekerkoetter, E., Mitani, Y., Gurtner, G. C., Sarnow, P., Rabinovitch, M. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J. Exp. Med. 211: 263-280, 2014. [PubMed: 24446489] [Full Text: https://doi.org/10.1084/jem.20111741]
Thomson, J. R., Machado, R. D., Pauciulo, M. W., Morgan, N. V., Humbert, M., Elliott, G. C., Ward, K., Yacoub, M., Mikhail, G., Rogers, P., Newman, J., Wheeler, L., and 13 others. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J. Med. Genet. 37: 741-745, 2000. [PubMed: 11015450] [Full Text: https://doi.org/10.1136/jmg.37.10.741]
Tsang, H. T. H., Edwards, T. L., Wang, X., Connell, J. W., Davies, R. J., Durrington, H. J., O'Kane, C. J., Luzio, J. P., Reid, E. The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling. Hum. Molec. Genet. 18: 3805-3821, 2009. [PubMed: 19620182] [Full Text: https://doi.org/10.1093/hmg/ddp324]