Human Molecular Genetics, 2003, Vol. 12, No. 5 473-482
© 2003 Oxford University Press
A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2
1Department of Molecular Genetics and Microbiology, 2Division of Laboratory Animal Resources and 3Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA, 4Clinical Genetics Section, University of Edinburgh, Edinburgh, EH4 2XU, UK and 5Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA
Received October 9, 2002; Accepted December 31, 2002
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant disorder characterized by the age-dependent development of focal arteriovenous malformations and telangiectases. HHT type 2 is caused by loss of function mutations in activin receptor-like kinase 1 (ACVRL1 or ALK1). However, the factors that initiate lesion formation and those that influence disease progression remain unknown. Because heterozygous mice contain the appropriate genotype for an animal model of this disorder, mice heterozygous for a loss-of-function mutation in Acvrl1 were carefully examined for an HHT-like phenotype. These mice developed age-dependent vascular lesions in the skin, extremities, oral cavity and in the internal organs (lung, liver, intestine, spleen and brain), similar to those seen in HHT patients. Major histopathological features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage and fibrosis. Similar to HHT patients, the mice also exhibited gastrointestinal bleeding, as evidenced by positive fecal occult blood tests. An Acvrl1+/- mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. The similarity of affected organs, age-dependent penetrance, histological similarity of the lesions and recapitulation of a secondary phenotype suggest that the Acvrl1+/- mice are an appropriate animal model for the identification of additional genetic and environmental factors that cause pathology in HHT type 2 patients. In addition, studies utilizing this animal model can yield valuable information on the role of ALK1 in maintenance of adult vascular architecture including arteriovenous identity.
* To whom correspondence should be addressed at: Department of Molecular Genetics and Microbiology, Box 3175, Duke University Medical Center, Durham, NC 27710, USA. Tel: +1 9196843290; Fax: +1 9196819193; Email: march004{at}mc.duke.edu
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