Brief review
Endoglin-deficient Mice, a Unique Model to Study Hereditary Hemorrhagic Telangiectasia

https://doi.org/10.1016/S1050-1738(01)00062-7Get rights and content

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by dilated vessels and arteriovenous malformations. Phenotypic heterogeneity, such as age of onset, severity of disease and organ involvement, is explained in part by two genes being mutated, endoglin (HHT1) and ALK-1 (HHT2). Haploinsufficiency is the mechanism responsible for HHT. This implies that position and type of mutations cannot explain heterogeneity, because mutant proteins are not expressed at the cell surface and consequently cannot interfere with normal function. Based on this model, we generated mice expressing only one allele of endoglin, but in two different inbred strains, 129/Ola and C57BL/6. Phenotypic heterogeneity was also observed among the HHT mice and was very dependent on the genetic background. Our data strongly suggest that additional genes, contributed by the 129/Ola strain, are responsible for the vascular anomalies associated with HHT. The murine model is faithful to the human disease and should allow us to identify the modifier genes of HHT as well as to test potential therapeutic interventions.

Section snippets

Important Role for Endoglin in Vascular Development and Homeostasis

How can reduced levels of functional endoglin, and/or ALK-1, on vascular endothelium lead to abnormally dilated vessels and HHT? Human endoglin (CD105) is a homodimeric transmembrane glycoprotein constitutively expressed at high levels on endothelial cells of capillaries, veins and arteries Gougos and Letarte 1990, Letarte et al. 1995. Endoglin associates with ligand- binding receptors for several members of the transforming growth factor β (TGF-β) superfamily (Barbara et al. 1999). Endoglin

Development of a Murine Model of HHT

The haploinsufficiency associated with HHT1 implies that mutation at a single allele leads to a loss of function and that engineering Endoglin hemizygosity in mice could yield an animal model of HHT. Endoglin (End)+/− mice were produced by backcrosses, starting with chimeric founder animals, onto 129/Ola and C57BL/6 inbred strains (Bourdeau et al. 1999). The End+/− 129/Ola mice are inbred while the End+/− C57BL/6 mice are of mixed genotype (C57BL/6 and 129/Ola). Intercrosses between these

Murine HHT is Strain Dependent and Suggests Modifier Genes Effects

HHT manifestations were highly heterogeneous in mice. We observed a population of 202 End+/− mice, all potentially disease-prone because of their mutated Endoglin allele, but only 59 developed HHT. The age of onset, judged by external signs, ranged from 1 week to 18 months with the majority developing HHT before 9 months. Of the 202 End+/− mice, only 22 were inbred 129/Ola, as this strain breeds poorly. 16 were (129/Ola x C57BL/6) F1; 59 were C57BL/6 backcrosses (N2) with 50% of mice

Human and Murine HHT; Similarities and Differences

We report a group of patients seen at the Toronto HHT Clinic who were diagnosed clinically and compare them to End+/− mice with HHT (Figure 4). Of the 197 patients with HHT, the majority had mucocutaneous telangiectases (93%) and recurrent spontaneous nose bleeds (85%); 38% had pulmonary AVMs, 7% had cerebral AVMs, 9% had liver AVMs and 17% had chronic GI bleeding. The expression of disease in our HHT population is similar to that in another previously published large series (Plauchu et al.

How Useful is the HHT Mouse?

Clinical studies of human HHT revealed phenotypic heterogeneity, which is explained in part by two genes, Endoglin and ALK-1. Expression studies showed that haploinsufficiency is the mechanism responsible for HHT, indicating that disease heterogeneity cannot be explained by position and type of mutations. As all mutant proteins studied to date cannot reach the cell surface, they cannot interfere with the normal function of endoglin (and likely ALK-1). A proportion of the mice expressing a

Acknowledgements

We acknowledge all patients who participated in the studies. We thank Dr. IR Wanless for pathological expertise, Ms. Urszula Cymerman, and Sonia Vera for performing mutation analysis and protein expression studies and Ms. Shelley Kennedy for help with genetic counselling and preparation of pedigrees. We thank Mr. Sigmund Kaw and Ms. Merry-Lynn McDonald for technical assistance and Ms. Lily Morikawa, for her invaluable help in preparing sections from the various murine tissues. We are grateful

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