Brief reviewEndoglin-deficient Mice, a Unique Model to Study Hereditary Hemorrhagic Telangiectasia
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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2016, Molecular OncologyCitation Excerpt :Interestingly, mutations in BMP9 have been identified in individuals with a vascular disorder phenotypically overlapping with HHT (Wooderchak-Donahue et al., 2013). Alk1+/− and Eng+/− mice exhibit abnormal vascular phenotypes reminiscent of those of HHT patients, while Alk1−/− and Eng−/− mice die at E11 because of major angiogenesis defects (Bourdeau et al., 2000; Srinivasan et al., 2003). BMP9-knockout neonates and adult mice show an abnormal lymphatic vasculature and a decrease in draining efficiency (Levet et al., 2013), while other vascular functions of BMP9 during embryogenesis and development are compensated by BMP10, the closest homolog for BMP9 sharing 65% similarity at the protein level (Ricard et al., 2012; Chen et al., 2013).