International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F59 Development of a Mouse Model for Hereditary Hemorrhagic Telangiectasia Type II

Jing Yu1, Roger McLendon2, En Li3, Paul Oh, Travis J.1, Riney, Rosemary Akhurst4, Robert J. Lechleider5, Austin Diamond6, Helen Arthur6, Raju Kucherlapati7, Winfried Edelmann7, Marie Lia7, Doug Marchuk1. Genetics Dept., Duke University, Durham, NC 27710; 2Pathology Dept, Duke University, Durham, NC 27710; 3Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; 4Onyx Pharmaceuticals, Richmond, CA 94806; 5NCI, National Institutes of Health, Bethesda, MD 20892-5055; 6School of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, NE2 4HH, UK; 7Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461A

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular lesions in a variety of organs. The disorder exhibits variable expressivity and age-dependent penetrance which is nearly complete by the fourth decade. Currently two genes---endoglin (Eng) and activin-receptor like kinase 1 (Alk1)---have been identified that when mutated, give rise to HHT types I and II respectively. We are developing a mouse model of HHT type II that is heterozygous at the Alk1 gene. The homozygous knockout (KO) mouse is embryonic lethal but heterozygotes as of yet show no obvious phenotype.

We have crossed the heterozygous Alk1 KO mouse into various genetic backgrounds, seeking the seeking other genetic and environmental factors that might modulate the HHT phenotype. The crosses are based on the following hypothesis: vascular lesions in HHT patients may be caused by LOH (loss of heterozygosity) at the Alk1 site, deficiencies of other factors in the Tgf beta signaling pathway, and/or environmental elements such as increased thrombotic foci which may initiate vascular lesion development.

To test the two-hit hypothesis of HHT, we have crossed Alk1 heterozygotes with homozygous mutant Msh2 or Msh6 mice, which are deficient in DNA mismatch repair. To investigate the involvement of Tgf beta signaling factors in the development of the vascular lesions, Alk1 mice have been crossed into the Tgf beta1 or Smad1 heterozygous background. Alk1 heterozygous mice has also been crossed into an Eng heterozygous background to determine whether there is any additive effect of the two mutations. Alk1 mice have been crossed with t-PA (tissue plasminogen activator) or u-PA (urokinase plasminogen activator) deficient mice, which have an increased thrombosis tendency, to see if thrombosis triggers the vascular lesion phenotype.

Neovascularization of tumors and wound healing are being examined in the Alk1 heterozygous mice to look for other effects of the mutation on adult vasculogenesis.

 


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