Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia.

Lidia Ruiz-Llorente, Elisa Chiapparino, Sara Plumitallo, Cesare Danesino, Pinar Bayrak-Toydemir, Fabio Pagella, Guido Manfredi, Carmelo Bernabeu, Luca Jovine, Carla Olivieri

Journal: Gene 2019;696():33-39

PMID: 30763665

Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: [email protected].; Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy. Electronic address: [email protected].; Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy; IRCCS Fondazione Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy. Electronic address: [email protected].; Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy; IRCCS Fondazione Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy. Electronic address: [email protected].; ARUP Institute for Clinical and Experimental Pathology, Department of Pathology, University of Utah, Salt Lake City, UT, USA. Electronic address: [email protected].; Head and Neck Department, ENT Unit, IRCCS Fondazione Policlinico "San Matteo", Piazzale Golgi 2, 27100 Pavia, Italy. Electronic address: [email protected].; UOC Gastroenterology and Endoscopy Unit, ASST, Ospedale Maggiore, 26013 Crema, CR, Italy. Electronic address: [email protected].; Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: [email protected].; Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Medicinaren 25 Neo, SE-141 83 Huddinge, Sweden. Electronic address: [email protected].; Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy. Electronic address: [email protected].

DOI: 10.1016/j.gene.2019.02.016

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MeSH Terms: Adult, Child, Cysteine, Endoglin, Exons, Female, Haploinsufficiency, Humans, Italy, Male, Middle Aged, Pedigree, Protein Domains, Protein Folding, Signal Transduction, Telangiectasia, Hereditary Hemorrhagic, Young Adult