Genetic and Molecular Basis for Hereditary Hemorrhagic Telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that predisposes patients to develop direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although the genes responsible for the majority of HHT cases have been known for nearly 20 years, molecular and cellular mechanisms underlying pathogenesis are poorly understood, and the genetic and/or environmental factors that confer variability to age of onset and expressivity of HHT remain unknown. Herein, we review the genetics and genotype/ phenotype correlations associated with HHT and summarize data from animal and cell culture models that lend insight into disease mechanism. At present, therapies available to HHT patients for treatment of visceral AVMs are primarily surgical, although antiangiogenic agents show some efficacy in treatment of telangiectasias, epistaxis, and liver AVMs. In light of new mechanistic data on disease pathogenesis, we consider possible approaches for development of more targeted therapeutics for HHT patients.

Bone morphogenetic protein receptor signal transduction in human disease

“…HHT is a rare autosomal dominant genetic disorder leading to vascular malformations that result in direct connections between arteries and veins. The disease is characterized by mucocutaneous telangiectases and arteriovenous malformations of the gastrointestinal tract, liver, lung, and brain . The most prevalent symptom of HHT is nosebleeds, which radically affects the quality of life of the patient.…”

“…Mutations in ENG (encoding Endoglin), ACVRL1 ( encoding ALK1) and SMAD4 cause HHT1 (MIM: 187300), HHT2 (MIM: 600376), and the combined Juvenile Polyposis/HHT (MIM: 175050) syndrome, respectively . While mutations in ENG and ACVRL1 represent 80–85% of HHT cases, only 2% of HHT is caused by mutations in SMAD4 . To date, no causative mutations have been identified in patients with HHT3 (MIM: 601101) and HHT4 (MIM: 610655).…”

“…Mice with heterozygous inactivating mutations of these genes exhibit particular vascular phenotypes which do not recapitulate the human disease completely. Therefore, conditional knockout mice, which recapitulate the specific arteriovenous malformations observed in patients, represent the most accepted animal models to study HHT . Current therapies for HHT rely on inhibiting angiogenesis by means of Bevacizumab (VEGF inhibitor) or by increasing clotting through the use of Thalidomide or antifibrinolytics .…”

ALK1 signaling in development and disease: new paradigms

“…Although HHT is an autosomal dominant condition and most mutations do not function as dominant negatives (reviewed in [84]), it remains unclear whether HHT-associated AVMs result from haploinsufficiency or a second somatic hit and resulting mosaic loss-of-function. In support of the second somatic hit theory, heterozygous Acvrl1 mice develop dilated vessels and hemorrhage with incomplete penetrance [85], and heterozygous Eng mice develop dilated vessels, hemorrhage, and AVMs with incomplete penetrance, but only on the 129/Ola background [77, 86], which is predisposed to vascular defects [87].…”