Melanie A. Baldwin

Journal Article Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function Get access Kimberly A. McAllister, Kimberly A. McAllister Search for other works by this author on: Oxford Academic PubMed Google Scholar Melanie A. Baldwin, Melanie A. Baldwin Search for other works by this author on: Oxford Academic PubMed Google Scholar Arun K. Thukkani, Arun K. Thukkani Search for other works by this author on: Oxford Academic PubMed Google Scholar Carol J. Gallione, Carol J. Gallione Search for other works by this author on: Oxford Academic PubMed Google Scholar Jonathan N. Berg, Jonathan N. Berg 1Department of Human Genetics, University of EdinburghWestern General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Mary E. Porteous, Mary E. Porteous 1Department of Human Genetics, University of EdinburghWestern General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Allan E. Guttmacher, Allan E. Guttmacher 2Department of Pediatrics, University of Vermont College of MedicineBurlington, VT 05401, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Douglas A. Marchuk Douglas A. Marchuk * *To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 4, Issue 10, October 1995, Pages 1983–1985, https://doi.org/10.1093/hmg/4.10.1983 Published: 01 October 1995 Article history Received: 08 May 1995 Revision received: 10 July 1995 Accepted: 10 July 1995 Published: 01 October 1995

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent hemorrhage from the sites of vascular lesions. Two genes have been identified for HHT. Endoglin, a TGF-beta binding protein which maps to chromosome 9q3, is the gene for HHT1. The type and location of most of the previously described mutations in the endoglin (ENG) gene suggested a dominant-negative model of receptor-complex dysfunction for the molecular basis of this disorder. In this article we describe 11 novel ENG mutations in HHT kindreds, which include missense and splice-site mutations. Two identical missense mutations in unrelated families disrupt the start codon of the gene. In addition, some frameshift and nonsense mutations lead to very low or undetectable levels of transcript from the mutant allele. These combined data suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent hemorrhage from the sites of vascular lesions. Two genes have been identified for HHT. Endoglin, a TGF-β binding protein which maps to chromosome 9q3, is the gene for HHT1. The type and location of most of the previously described mutations in the endoglin (ENG) gene suggested a dominant-negative model of receptor–complex dysfunction for the molecular basis of this disorder. In this article we describe 11 novel ENG mutations in HHT kindreds, which include missense and splice-site mutations. Two identical missense mutations in unrelated families disrupt the start codon of the gene. In addition, some frameshift and nonsense mutations lead to very low or undetectable levels of transcript from the mutant allele. These combined data suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT. Hum Mutat 11:286–294, 1998. © 1998 Wiley-Liss, Inc.