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Gene. 2018 Mar 20;647:85-92. doi: 10.1016/j.gene.2018.01.007. Epub 2018 Jan 4.

Functional analysis of a novel ENG variant in a patient with hereditary hemorrhagic telangiectasia (HHT) identifies a new Sp1 binding-site.

Author information

1
Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy. Electronic address: sara.plumitallo01@univerisitadipavia.it.
2
Centro de Investigaciones Biológicas - Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, Calle Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: lruiz.llorente@cib.csic.es.
3
Centro de Investigaciones Biológicas - Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, Calle Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: langa.poza@cib.csic.es.
4
Physics Department, Radiation Biophysics and Radiobiology Lab, University of Pavia, Via Bassi 6, 27100 Pavia, Italy. Electronic address: jacopo.morini@unipv.it.
5
Physics Department, Radiation Biophysics and Radiobiology Lab, University of Pavia, Via Bassi 6, 27100 Pavia, Italy. Electronic address: gabriele.babini@unipv.it.
6
Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: donata.cappelletti@unipv.it.
7
Cardiothoracic-Vascular Department, Cardiology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: l.scelsi@smatteo.pv.it.
8
Cardiothoracic-Vascular Department, Cardiology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: grecale1985@gmail.com.
9
Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy; Genetic Counselling Service, IRCCS Fondazione Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy. Electronic address: cidi@unipv.it.
10
Centro de Investigaciones Biológicas - Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, Calle Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: bernabeu.c@cib.csic.es.
11
Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy. Electronic address: carla.olivieri@unipv.it.

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease, with an autosomal dominant inheritance and a worldwide incidence of about 1: 5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG or ACVRL1, which code for ENDOGLIN and Activin A Receptor Type II-Like Kinase 1 (ALK1), belonging to the TGF-β/BMP signalling pathway. Typical HHT clinical features are mucocutaneous telangiectases, arteriovenous malformations, spontaneous and recurrent epistaxis, as well as gastrointestinal bleedings. An additional, but less frequent, clinical manifestation in some HHT patients is the presence of Pulmonary Arterial Hypertension (PAH). The aim of this work is to describe the functional role of a novel ENG intronic variant found in a patient affected by both HHT and PAH, in order to assess whether it has a pathogenic role. We proved that the variant lies in a novel binding-site for the transcription factor Sp1, known to be involved in the regulation of ENG and ACVRL1 transcription. We confirmed a pathogenic role for this intronic variant, as it significantly reduces ENG transcription by affecting this novel Sp1 binding-site.

KEYWORDS:

ENG transcription; Intronic variant; Pulmonary arterial hypertension; Rendu-Osler-Weber syndrome

PMID:
29305977
DOI:
10.1016/j.gene.2018.01.007
[Indexed for MEDLINE]

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