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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1951-1954.
Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-05-1834.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Brief report
Functional analysis of mutations in the kinase domain of the TGF- receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia
Yi Gu,
Peng Jin,
Long Zhang,
Xingang Zhao,
Xia Gao,
Yuanheng Ning,
Anming Meng, and
Ye-Guang Chen
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, the Laboratory of Molecular Cell Biology, the Laboratory of Developmental Biology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China.
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.
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