Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding， skin and mucosa telangiectasias， and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients， HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes， which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1)， respectively， both belonging to the TGF-β/BMP signaling pathway. In this work， we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family， all ... More
Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding， skin and mucosa telangiectasias， and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients， HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes， which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1)， respectively， both belonging to the TGF-β/BMP signaling pathway. In this work， we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family， all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact， transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression.
