Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) is a vascular genetic disease characterized by autosomal dominant model of inheritance, with a prevalence of 1:5000-8000 individuals worldwide. Genes associated with the disease are ENG, ACVRL1, SMAD4, and GDF2. They are all involved in the TGF-β/BMP signaling pathway. One of the four clinical signs of HHT is the presence of arteriovenous malformations in lungs, liver, and central nervous system. Matrix Gla Protein (MGP) is a gene located on chromosome 12 encoding for the homonymous extracellular protein which seems to bind and inhibit BMP2 and BMP4, regulating ALK1 and VEGF expression. Recessive mutations in this gene are responsible for Keutel Syndrome. According to literature data, it seems to play a protective role in the development of pulmonary arteriovenous malformations (pAVMs) in a HHT mouse model. Purpose of the study: to investigate if variants in MGP can affect the HHT phenotype, focusing on the presence of pAVMs. Materials and methods: We performed a Sanger Sequencing analysis on 40 HHT patients presenting pAVMs and 11 relatives affected by the disease but without pAVMs. The whole gene, including intronic regions and 5’ UTR and 3’ UTR, was screened. We used online tools such as Varsome and GnomAD to perform an in silico evaluation of the variants observed. Results: Preliminary results obtained from 75% of gene sequencing (including the whole coding region) show the presence of more than 8 variants. Two of them are present in gnomAD (benign variants) and are found both in hetero- and homozygous state, according to the database. Of interest, the c.-63 G>A variant was found in homozygous state only in patients with pAVMs (17,9%). The functional role of the variants will be further investigated after the completion of this study. Conclusions: Our preliminary results suggest a role of the MGP gene in affecting the HHT phenotype with a focus on the presence/ absence of pAVMs. The mechanism by which this occurs remains unknown, but it can be related to the regulation of HHT-related pathways involving BMP4 and VEGF mediated by MGP.

Modifier genes in HHT: preliminary results of MGP sequencing.

F. Pagella;E. Matti;C. Olivieri
2021

Abstract

Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) is a vascular genetic disease characterized by autosomal dominant model of inheritance, with a prevalence of 1:5000-8000 individuals worldwide. Genes associated with the disease are ENG, ACVRL1, SMAD4, and GDF2. They are all involved in the TGF-β/BMP signaling pathway. One of the four clinical signs of HHT is the presence of arteriovenous malformations in lungs, liver, and central nervous system. Matrix Gla Protein (MGP) is a gene located on chromosome 12 encoding for the homonymous extracellular protein which seems to bind and inhibit BMP2 and BMP4, regulating ALK1 and VEGF expression. Recessive mutations in this gene are responsible for Keutel Syndrome. According to literature data, it seems to play a protective role in the development of pulmonary arteriovenous malformations (pAVMs) in a HHT mouse model. Purpose of the study: to investigate if variants in MGP can affect the HHT phenotype, focusing on the presence of pAVMs. Materials and methods: We performed a Sanger Sequencing analysis on 40 HHT patients presenting pAVMs and 11 relatives affected by the disease but without pAVMs. The whole gene, including intronic regions and 5’ UTR and 3’ UTR, was screened. We used online tools such as Varsome and GnomAD to perform an in silico evaluation of the variants observed. Results: Preliminary results obtained from 75% of gene sequencing (including the whole coding region) show the presence of more than 8 variants. Two of them are present in gnomAD (benign variants) and are found both in hetero- and homozygous state, according to the database. Of interest, the c.-63 G>A variant was found in homozygous state only in patients with pAVMs (17,9%). The functional role of the variants will be further investigated after the completion of this study. Conclusions: Our preliminary results suggest a role of the MGP gene in affecting the HHT phenotype with a focus on the presence/ absence of pAVMs. The mechanism by which this occurs remains unknown, but it can be related to the regulation of HHT-related pathways involving BMP4 and VEGF mediated by MGP.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11571/1447604
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact