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Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213

SIMPLE SUMMARY: Neurofibromatosis type 1 and Moyamoya disease can be associated in Moyamoya syndrome (MMS), which causes cerebral arteriopathy consisting of a progressive steno-occlusion of the intracranial arteries. Here, we investigated if rare variants of RNF213, the most common genetic risk fact...

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Autores principales: Ognibene, Marzia, Scala, Marcello, Iacomino, Michele, Schiavetti, Irene, Madia, Francesca, Traverso, Monica, Guerrisi, Sara, Di Duca, Marco, Caroli, Francesco, Baldassari, Simona, Tappino, Barbara, Romano, Ferruccio, Uva, Paolo, Vozzi, Diego, Chelleri, Cristina, Piatelli, Gianluca, Diana, Maria Cristina, Zara, Federico, Capra, Valeria, Pavanello, Marco, De Marco, Patrizia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047491/
https://www.ncbi.nlm.nih.gov/pubmed/36980803
http://dx.doi.org/10.3390/cancers15061916
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author Ognibene, Marzia
Scala, Marcello
Iacomino, Michele
Schiavetti, Irene
Madia, Francesca
Traverso, Monica
Guerrisi, Sara
Di Duca, Marco
Caroli, Francesco
Baldassari, Simona
Tappino, Barbara
Romano, Ferruccio
Uva, Paolo
Vozzi, Diego
Chelleri, Cristina
Piatelli, Gianluca
Diana, Maria Cristina
Zara, Federico
Capra, Valeria
Pavanello, Marco
De Marco, Patrizia
author_facet Ognibene, Marzia
Scala, Marcello
Iacomino, Michele
Schiavetti, Irene
Madia, Francesca
Traverso, Monica
Guerrisi, Sara
Di Duca, Marco
Caroli, Francesco
Baldassari, Simona
Tappino, Barbara
Romano, Ferruccio
Uva, Paolo
Vozzi, Diego
Chelleri, Cristina
Piatelli, Gianluca
Diana, Maria Cristina
Zara, Federico
Capra, Valeria
Pavanello, Marco
De Marco, Patrizia
author_sort Ognibene, Marzia
collection PubMed
description SIMPLE SUMMARY: Neurofibromatosis type 1 and Moyamoya disease can be associated in Moyamoya syndrome (MMS), which causes cerebral arteriopathy consisting of a progressive steno-occlusion of the intracranial arteries. Here, we investigated if rare variants of RNF213, the most common genetic risk factor for Moyamoya, could act as genetic modifiers of MMS phenotype in a pediatric cohort of patients. Next-generation sequencing of NF1 and RNF213 genes was performed on genomic DNA extracted from patients’ blood. We found that in MMS patients, RNF213 does not appear to modify Moyamoya occurrence risk. Rather, it is more probable that the loss of neurofibromin 1, the protein encoded by the NF1 gene, is responsible by itself for the excessive proliferation of vascular smooth muscle cells causing arterial stenosis. Further studies in larger cohorts of patients are necessary to confirm these findings and to identify other genetic factors in order to increase our understanding of MMS pathogenesis. ABSTRACT: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in NF1 gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events. RNF213 gene mutations have been associated with MMD, so we investigated whether rare variants of RNF213 could act as genetic modifiers of MMS phenotype in a pediatric cohort of 20 MMS children, 25 children affected by isolated MMD and 47 affected only by isolated NF1. By next-generation re-sequencing (NGS) of patients’ DNA and gene burden tests, we found that RNF213 seems to play a role only for MMD occurrence, while it does not appear to be involved in the increased risk of Moyamoya for MMS patients. We postulated that the loss of neurofibromin 1 can be enough for the excessive proliferation of vascular smooth muscle cells, causing Moyamoya arteriopathy associated with NF1. Further studies will be crucial to support these findings and to elucidate the possible role of other genes, enhancing our knowledge about pathogenesis and treatment of MMS.
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spelling pubmed-100474912023-03-29 Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213 Ognibene, Marzia Scala, Marcello Iacomino, Michele Schiavetti, Irene Madia, Francesca Traverso, Monica Guerrisi, Sara Di Duca, Marco Caroli, Francesco Baldassari, Simona Tappino, Barbara Romano, Ferruccio Uva, Paolo Vozzi, Diego Chelleri, Cristina Piatelli, Gianluca Diana, Maria Cristina Zara, Federico Capra, Valeria Pavanello, Marco De Marco, Patrizia Cancers (Basel) Article SIMPLE SUMMARY: Neurofibromatosis type 1 and Moyamoya disease can be associated in Moyamoya syndrome (MMS), which causes cerebral arteriopathy consisting of a progressive steno-occlusion of the intracranial arteries. Here, we investigated if rare variants of RNF213, the most common genetic risk factor for Moyamoya, could act as genetic modifiers of MMS phenotype in a pediatric cohort of patients. Next-generation sequencing of NF1 and RNF213 genes was performed on genomic DNA extracted from patients’ blood. We found that in MMS patients, RNF213 does not appear to modify Moyamoya occurrence risk. Rather, it is more probable that the loss of neurofibromin 1, the protein encoded by the NF1 gene, is responsible by itself for the excessive proliferation of vascular smooth muscle cells causing arterial stenosis. Further studies in larger cohorts of patients are necessary to confirm these findings and to identify other genetic factors in order to increase our understanding of MMS pathogenesis. ABSTRACT: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in NF1 gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events. RNF213 gene mutations have been associated with MMD, so we investigated whether rare variants of RNF213 could act as genetic modifiers of MMS phenotype in a pediatric cohort of 20 MMS children, 25 children affected by isolated MMD and 47 affected only by isolated NF1. By next-generation re-sequencing (NGS) of patients’ DNA and gene burden tests, we found that RNF213 seems to play a role only for MMD occurrence, while it does not appear to be involved in the increased risk of Moyamoya for MMS patients. We postulated that the loss of neurofibromin 1 can be enough for the excessive proliferation of vascular smooth muscle cells, causing Moyamoya arteriopathy associated with NF1. Further studies will be crucial to support these findings and to elucidate the possible role of other genes, enhancing our knowledge about pathogenesis and treatment of MMS. MDPI 2023-03-22 /pmc/articles/PMC10047491/ /pubmed/36980803 http://dx.doi.org/10.3390/cancers15061916 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ognibene, Marzia
Scala, Marcello
Iacomino, Michele
Schiavetti, Irene
Madia, Francesca
Traverso, Monica
Guerrisi, Sara
Di Duca, Marco
Caroli, Francesco
Baldassari, Simona
Tappino, Barbara
Romano, Ferruccio
Uva, Paolo
Vozzi, Diego
Chelleri, Cristina
Piatelli, Gianluca
Diana, Maria Cristina
Zara, Federico
Capra, Valeria
Pavanello, Marco
De Marco, Patrizia
Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
title Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
title_full Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
title_fullStr Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
title_full_unstemmed Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
title_short Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
title_sort moyamoya vasculopathy in neurofibromatosis type 1 pediatric patients: the role of rare variants of rnf213
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047491/
https://www.ncbi.nlm.nih.gov/pubmed/36980803
http://dx.doi.org/10.3390/cancers15061916
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