{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:09:47Z","timestamp":1791407387861,"version":"4.3.3"},"reference-count":23,"publisher":"BMJ","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2000,10,1]]},"abstract":"<jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (<jats:italic>BMPR2), <\/jats:italic>a component of the transforming growth factor beta (TGF-\u03b2) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for<jats:italic> BMPR2<\/jats:italic> gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec sec-type=\"methods\">\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron\/exon boundaries of the <jats:italic>BMPR2<\/jats:italic> gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>We found a total of 11 different heterozygous germline mutations of the<jats:italic>BMPR2<\/jats:italic> gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the<jats:italic>BMPR2<\/jats:italic> gene in sporadic PPH.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSION<\/jats:title>\n                  <jats:p>The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of<jats:italic>BMPR2<\/jats:italic> mutations, has important implications for patient management and screening of relatives.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.37.10.741","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T06:37:59Z","timestamp":1027751879000},"page":"741-745","source":"Crossref","is-referenced-by-count":614,"title":["Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-\u03b2 family"],"prefix":"10.1136","volume":"37","author":[{"given":"Jennifer R","family":"Thomson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv D","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W","family":"Pauciulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil V","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Humbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg C","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdi","family":"Yacoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada","family":"Mikhail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Higenbottam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Simon R","family":"Gibbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Egan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Crozier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Peacock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Allcock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Corris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E","family":"Loyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C","family":"Trembath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C","family":"Nichols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2000,10,1]]},"reference":[{"key":"2025100522021166000_37.10.741.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199701093360207"},{"key":"2025100522021166000_37.10.741.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)02111-4"},{"key":"2025100522021166000_37.10.741.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199207093270203"},{"key":"2025100522021166000_37.10.741.4","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.70.4.366"},{"key":"2025100522021166000_37.10.741.5","doi-asserted-by":"crossref","first-page":"216","DOI":"10.7326\/0003-4819-107-2-216","article-title":"Primary pulmonary hypertension. A national prospective study.","volume":"107","author":"Rich","year":"1987","journal-title":"Ann Intern Med"},{"key":"2025100522021166000_37.10.741.6","first-page":"194","article-title":"Familial primary pulmonary hypertension: clinical patterns.","volume":"129","author":"Loyd","year":"1984","journal-title":"Am Rev Respir Dis"},{"key":"2025100522021166000_37.10.741.7","unstructured":"Machado RD, Pauciulo MW, Fretwell N, Veal C, Thomson JR, Guell CV, Aldred M, Brannon CA, the International PPH Consortium, Trembath RC, Nichols WC. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension.Genomics (in press).."},{"key":"2025100522021166000_37.10.741.8","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-277"},{"key":"2025100522021166000_37.10.741.9","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.95.12.2603"},{"key":"2025100522021166000_37.10.741.10","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1164\/ajrccm.161.3.9906051","article-title":"Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3 cM region on chromosome 2q33.","volume":"161","author":"Deng","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2025100522021166000_37.10.741.11","unstructured":"The International PPH Consortium, Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in a TGF-\u03b2 receptor,BMPR2, are the cause of familial primary pulmonary hypertension. Nat Genet (in press).."},{"key":"2025100522021166000_37.10.741.12","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1101\/gad.14.6.627","article-title":"Controlling TGF-\u03b2 signaling.","volume":"14","author":"Massague","year":"2000","journal-title":"Genes Dev"},{"key":"2025100522021166000_37.10.741.13","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1164\/ajrccm\/138.4.952","article-title":"Heterogeneity of pathologic lesions in familial primary pulmonary hypertension.","volume":"138","author":"Loyd","year":"1988","journal-title":"Am Rev Respir Dis"},{"key":"2025100522021166000_37.10.741.14","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.80.5.1198"},{"key":"2025100522021166000_37.10.741.15","doi-asserted-by":"publisher","DOI":"10.1378\/chest.108.4.973"},{"key":"2025100522021166000_37.10.741.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005043421807"},{"key":"2025100522021166000_37.10.741.17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1910"},{"key":"2025100522021166000_37.10.741.18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ng0598-17","article-title":"HNPCC associated with germline mutation in the TGF-\u03b2 type II receptor gene.","volume":"19","author":"Lu","year":"1998","journal-title":"Nat Genet"},{"key":"2025100522021166000_37.10.741.19","doi-asserted-by":"publisher","DOI":"10.4065\/73.1.37"},{"key":"2025100522021166000_37.10.741.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199608293350901"},{"key":"2025100522021166000_37.10.741.21","unstructured":"Thomson JR, Trembath RC. Primary pulmonary hypertension: the pressure rises for the gene. J Clin Pathol(in press).."},{"key":"2025100522021166000_37.10.741.22","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/0735-1097(91)90688-6","article-title":"Clinical and pathologic manifestations of pulmonary vascular disease in the toxic oil syndrome.","volume":"18","author":"Gomez-Sanchez","year":"1991","journal-title":"J Am Coll Cardiol"},{"key":"2025100522021166000_37.10.741.23","doi-asserted-by":"publisher","DOI":"10.1097\/00062752-199809000-00005"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.37.10.741","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T05:02:18Z","timestamp":1759726938000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.37.10.741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,10,1]]},"references-count":23,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2000,10,1]]},"published-print":{"date-parts":[[2000,10,1]]}},"alternative-id":["10.1136\/jmg.37.10.741"],"URL":"https:\/\/doi.org\/10.1136\/jmg.37.10.741","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,10,1]]}}}