Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia

Autor: Kara B. Anthony, Carol J. Gallione, Douglas A. Marchuk, Eric Y. Yeh, David W. Johnson, Daniel J. Klaus, Jing Yu, Andreas Lux
Rok vydání: 1998
Předmět:
Zdroj: Human Mutation. 12:137-137
ISSN: 1098-1004
1059-7794
DOI: 10.1002/(sici)1098-1004(1998)12:2<137::aid-humu15>3.0.co;2-m
Popis: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized bymultisystemic vascular dysplasia and recurrent hemorrhage. One of the causative genes is the activinreceptor-like kinase-1 (ALK-1) gene located on chromosome 12q13. ALK-1 is an endothelial cell type Ireceptor for the TGF- superfamily of ligands. As a number of mutations have been identified in the kinasedomain of ALK-1, we initiated a mutation analysis specifically targeting the first four coding exons of ALK-1in 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 theextracellular and transmembrane domains. These mutations would grossly truncate the ALK-1 protein and arethus classic null alleles. Three new missense mutations within the exons encoding the extracellular domain, inaddition 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. Thecombined data suggest that both severe and subtle changes in the ALK-1 amino acid sequence can lead toreceptor dysfunction and result in the HHT disease phenotype.
Databáze: OpenAIRE
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