title: Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia.
abstract: Genetic studies in mouse and zebrafish have established the importance of activin receptor-like kinase 1 (ALK1) in formation and remodeling of blood vessels. Single-allele mutations in the ALK1 gene have been linked to the human type 2 hereditary hemorrhagic telangiectasia (HHT2). However, how these ALK1 mutations contribute to this disorder remains unclear. To explore the mechanism underlying effect of the HHT-related ALK1 mutations on receptor activity, we generated 11 such mutants and investigated their signaling activities using reporter assay in mammalian cells and examined their effect on zebrafish embryogenesis. Here we show that some of the HHT2-related mutations generate a dominant-negative effect whereas the others give rise to a null phenotype via loss of protein expression or receptor activity. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Xingang
authors.initials: X
authors.lastname: Zhao
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.forename: Yuanheng
authors.initials: Y
authors.lastname: Ning
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D047108:Embryonic Development / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
chemical_list: C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II