PUBLICATION
Functional analysis of mutations in the kinase domain of the TGF-β receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia
- Authors
- Gu, Y., Jin, P., Zhang, L., Zhao, X., Gao, X., Ning, Y., Meng, A., and Chen, Y.G.
- ID
- ZDB-PUB-051114-12
- Date
- 2006
- Source
- Blood 107(5): 1951-1954 (Journal)
- Registered Authors
- Jin, Peng, Meng, Anming, Zhang, Lixia
- Keywords
- none
- MeSH Terms
-
- Activin Receptors, Type I/genetics
- Activin Receptors, Type I/metabolism*
- Activin Receptors, Type II
- Animals
- COS Cells
- Chlorocebus aethiops
- Embryonic Development*/genetics
- Endothelium, Vascular/metabolism
- Genes, Dominant*
- Humans
- Mice
- Mutation*
- Protein Structure, Tertiary
- Telangiectasia, Hereditary Hemorrhagic/genetics
- Telangiectasia, Hereditary Hemorrhagic/metabolism*
- Zebrafish/embryology*
- Zebrafish/genetics
- PubMed
- 16282348 Full text @ Blood
Citation
Gu, Y., Jin, P., Zhang, L., Zhao, X., Gao, X., Ning, Y., Meng, A., and Chen, Y.G. (2006) Functional analysis of mutations in the kinase domain of the TGF-β receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood. 107(5):1951-1954.
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 while 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping