Cargando…

Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis

Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-β)/BMP signaling are linked to both sporadic and hereditary...

Descripción completa

Detalles Bibliográficos
Autores principales: Scimone, Concetta, Granata, Francesca, Longo, Marcello, Mormina, Enricomaria, Turiaco, Cristina, Caragliano, Antonio A., Donato, Luigi, Sidoti, Antonina, D’Angelo, Rosalia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352422/
https://www.ncbi.nlm.nih.gov/pubmed/32560555
http://dx.doi.org/10.3390/ijms21124321
_version_ 1783557634517893120
author Scimone, Concetta
Granata, Francesca
Longo, Marcello
Mormina, Enricomaria
Turiaco, Cristina
Caragliano, Antonio A.
Donato, Luigi
Sidoti, Antonina
D’Angelo, Rosalia
author_facet Scimone, Concetta
Granata, Francesca
Longo, Marcello
Mormina, Enricomaria
Turiaco, Cristina
Caragliano, Antonio A.
Donato, Luigi
Sidoti, Antonina
D’Angelo, Rosalia
author_sort Scimone, Concetta
collection PubMed
description Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-β)/BMP signaling are linked to both sporadic and hereditary phenotypes. However, the low incidence of inherited cases makes the genetic bases of the disease unclear. To increase this knowledge, we performed a whole exome sequencing on five patients, on DNA purified by peripheral blood. Variants were filtered based on frequency and functional class. Those selected were validated by Sanger sequencing. Genes carrying selected variants were prioritized to relate these genes with those already known to be linked to bAVM development. Most of the prioritized genes showed a correlation with the TGF-βNotch signaling and vessel morphogenesis. However, two novel pathways related to cilia morphogenesis and ion homeostasis were enriched in mutated genes. These results suggest novel insights on sporadic bAVM onset and confirm its genetic heterogeneity. The high frequency of germline variants in genes related to TGF-β signaling allows us to hypothesize bAVM as a complex trait resulting from the co-existence of low-penetrance loci. Deeper knowledge on bAVM genetics can improve personalized diagnosis and can be helpful with genotype–phenotype correlations.
format Online
Article
Text
id pubmed-7352422
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-73524222020-07-15 Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis Scimone, Concetta Granata, Francesca Longo, Marcello Mormina, Enricomaria Turiaco, Cristina Caragliano, Antonio A. Donato, Luigi Sidoti, Antonina D’Angelo, Rosalia Int J Mol Sci Article Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-β)/BMP signaling are linked to both sporadic and hereditary phenotypes. However, the low incidence of inherited cases makes the genetic bases of the disease unclear. To increase this knowledge, we performed a whole exome sequencing on five patients, on DNA purified by peripheral blood. Variants were filtered based on frequency and functional class. Those selected were validated by Sanger sequencing. Genes carrying selected variants were prioritized to relate these genes with those already known to be linked to bAVM development. Most of the prioritized genes showed a correlation with the TGF-βNotch signaling and vessel morphogenesis. However, two novel pathways related to cilia morphogenesis and ion homeostasis were enriched in mutated genes. These results suggest novel insights on sporadic bAVM onset and confirm its genetic heterogeneity. The high frequency of germline variants in genes related to TGF-β signaling allows us to hypothesize bAVM as a complex trait resulting from the co-existence of low-penetrance loci. Deeper knowledge on bAVM genetics can improve personalized diagnosis and can be helpful with genotype–phenotype correlations. MDPI 2020-06-17 /pmc/articles/PMC7352422/ /pubmed/32560555 http://dx.doi.org/10.3390/ijms21124321 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Scimone, Concetta
Granata, Francesca
Longo, Marcello
Mormina, Enricomaria
Turiaco, Cristina
Caragliano, Antonio A.
Donato, Luigi
Sidoti, Antonina
D’Angelo, Rosalia
Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis
title Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis
title_full Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis
title_fullStr Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis
title_full_unstemmed Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis
title_short Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis
title_sort germline mutation enrichment in pathways controlling endothelial cell homeostasis in patients with brain arteriovenous malformation: implication for molecular diagnosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352422/
https://www.ncbi.nlm.nih.gov/pubmed/32560555
http://dx.doi.org/10.3390/ijms21124321
work_keys_str_mv AT scimoneconcetta germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT granatafrancesca germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT longomarcello germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT morminaenricomaria germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT turiacocristina germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT caraglianoantonioa germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT donatoluigi germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT sidotiantonina germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis
AT dangelorosalia germlinemutationenrichmentinpathwayscontrollingendothelialcellhomeostasisinpatientswithbrainarteriovenousmalformationimplicationformoleculardiagnosis