BMPR2

Gene Facts

• HGNC Symbol: BMPR2 (HGNC:1078)
• HGNC Name: bone morphogenetic protein receptor type 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: PPH1
• Alias symbols: BRK-3, T-ALK, BMPR3, BMPR-II
• %HI: 1.48
• pLI: 1
• LOEUF: 0.38
• Cytoband: 2q33.1-q33.2
• Genomic Coordinates:

  GRCh37/hg19:	chr2:203241050-203432472
  GRCh38/hg38:	chr2:202376327-202567749

• MANE Select Transcript: NM_001204.7 ENST00000374580.10
• Function: On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Can also mediate signaling through the activation of the p38MAPK cascade (PubMed:12045205). Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates inducti... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-5367
• ClinGen Curation ID: CCID:006753
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 08/26/2020

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• pulmonary hypertension, primary, 1

HI Evidence

• PUBMED: 10903931
  Deng et al. (2000) genotyped 35 multiplex families with primary pulmonary hypertension (PPH) using 27 microsatellite markers. BMPR2 was identified as a positional candidate, and analysis of BMPR2 coding sequence identified seven presumed disease-causative mutations in nine families. A premature stop codon in exon 4 (c.507–510delCTTTinsAAA; p.C169X) was identified in three affected individuals from family PPH017. DNA samples were available for six unaffected individuals from this family who were presumably mutation negative. Zero carriers were reported for this family, although it is unclear whether i) all mutation positive family members presented with PPH, or ii) if obligate carriers were not available for DNA sequence analysis. A stopgain mutation more than 55 nucleotides upstream of the exon-intron boundary of the penultimate exon 12 (c.2617C>T; p.R873X) was identified in three affected individuals and two carriers in family PPH018. A frameshift deletion in exon 12 (c.2579delT; p.N861fsX10) was identified in six affected individuals and one carrier from family PPH015.
• PUBMED: 11015450
  Thomson et al. (2000) assessed 50 unrelated patients with a clinical diagnosis of primary pulmonary hypertension and no identifiable family history of disease for mutations in the coding sequence of BMPR2. De novo mutations in BMPR2 were identified in two patients, and included a frameshift deletion in exon 9 (c.1248delA), and a frameshift deletion occurring more than 55 nucleotides upstream of the exon-intron boundary of the penultimate exon 12 (c.2386delG). Paternity was confirmed in both families through the analysis of informative markers. Mutations resulting in a premature termination codon were identified in 8 additional patients (seven of unknown inheritance; one paternally transmitted). A nonsense mutation (R211X) was identified in a proband with primary pulmonary hyptertension and was not was not present in 150 normal chromosomes. Machado et al. (2001) identified the same mutation in 2 affected family members with PPH. Humbert et al. (2002; PMID:12358323) identified the same mutation in two sisters with PPH, and confirmed that the mutation was not present in 260 control chromosomes.

• HI Evidence Comments: Additional information includes: From GeneReviews: BMPR2 mutations are identified in ~75% of cases with hereditary pulmonary arterial hypertension (formerly known as primary pulmonary hypertension). Incomplete penetrance of BMPR2 mutations is well-described, and penetrance is estimated as 0.2. Penetrance is sex dependent, and ranges from 0.14 in males to 0.48 in females. Over 600 disease-causative mutations in BMPR2 are documented in HGMD professional as of July 2020, and include 100 stopgain mutations, >100 small frameshift deletions/insertions, and >70 large exon-spanning deletions. A de novo whole gene deletion of BMPR2 has been identified in a proband by MLPA analysis (Aldred et al. 2006; subject ID 21646). However, as the upstream and downstream boundaries of the rearrangement were not characterized, the full extent of deleted sequence is unknown. PMIDs 11115378 and 16429395 provide an extensive list of mutations identified in cases of pulmonary arterial hypertension.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity