Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online.

Journal Article (Journal Article)

Hereditary hemmorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dyplasia and recurrent hemorrhage. One of the causative genes is the activin receptor-like kinase-1 (ALK-1) gene located on chromosome 12q13. ALK-1 is an endothelial cell type I receptor for the TGF-beta superfamily of ligands. As a number of mutations have been identified in the kinase domain of ALK-1, we initiated a mutation analysis specifically targeting the first four coding exons of ALK-1 in order to determine if mutations in the extracellular and transmembrane domains are also present in HHT. Six new mutations have been identified. Three frameshift mutations were identified in exons encoding the extracellular and transmembrane domains. These mutations would grossly truncate the ALK-1 protein and are thus classic null alleles. Three new missense mutations within the exons encoding the extracellular domain, in addition to two previously described missense mutations, are located at or near highly conserved cysteines. These mutations may disrupt intra- or inter-molecular disulfide bridges required for ligand binding. The combined data suggest that both severe and subtle changes in the ALK-1 amino acid sequence can lead to receptor dysfunction and result in the HHT disease phenotype.

Full Text

Duke Authors

Cited Authors

  • Klaus, DJ; Gallione, CJ; Anthony, K; Yeh, EY; Yu, J; Lux, A; Johnson, DW; Marchuk, DA

Published Date

  • January 1, 1998

Published In

Volume / Issue

  • 12 / 2

Start / End Page

  • 137 -

PubMed ID

  • 10694922

International Standard Serial Number (ISSN)

  • 1059-7794

Digital Object Identifier (DOI)

  • 10.1002/(SICI)1098-1004(1998)12:2<137::AID-HUMU16>3.0.CO;2-J


  • eng

Conference Location

  • United States