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Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance
Wide comprehension of genetic features of cerebral cavernous malformations (CCM) represents the starting point to better manage patients and risk rating in relatives. The causative mutations spectrum is constantly growing. KRIT1, CCM2, and PDCD10 are the three loci to date linked to familial CCM dev...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246743/ https://www.ncbi.nlm.nih.gov/pubmed/30487773 http://dx.doi.org/10.3389/fneur.2018.00953 |
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author | Scimone, Concetta Donato, Luigi Katsarou, Zoe Bostantjopoulou, Sevasti D'Angelo, Rosalia Sidoti, Antonina |
author_facet | Scimone, Concetta Donato, Luigi Katsarou, Zoe Bostantjopoulou, Sevasti D'Angelo, Rosalia Sidoti, Antonina |
author_sort | Scimone, Concetta |
collection | PubMed |
description | Wide comprehension of genetic features of cerebral cavernous malformations (CCM) represents the starting point to better manage patients and risk rating in relatives. The causative mutations spectrum is constantly growing. KRIT1, CCM2, and PDCD10 are the three loci to date linked to familial CCM development, although germline mutations have also been detected in patients affected by sporadic forms. In this context, the main challenge is to draw up criteria to formulate genotype-phenotype correlations. Clearly, genetic factors determining incomplete penetrance of CCM need to be identified. Here, we report two novel intronic variants probably affecting splicing. Molecular screening of CCM genes was performed on DNA purified by peripheral blood. Coding exons and intron-exon boundaries were sequenced by the Sanger method. The first was detected in a sporadic patient and involves KRIT1. The second affects CCM2 and it is harbored by a woman with familial CCM. Interestingly, molecular analysis extended to both healthy and ill relatives allowed to estimate, for the first time, a penetrance for CCM2 lower than 100%, as to date reported. Moreover, heterogeneity of clinical manifestations among those affected carrying the same genotype further confirms involvement of modifier factors in CCM development. |
format | Online Article Text |
id | pubmed-6246743 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62467432018-11-28 Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance Scimone, Concetta Donato, Luigi Katsarou, Zoe Bostantjopoulou, Sevasti D'Angelo, Rosalia Sidoti, Antonina Front Neurol Neurology Wide comprehension of genetic features of cerebral cavernous malformations (CCM) represents the starting point to better manage patients and risk rating in relatives. The causative mutations spectrum is constantly growing. KRIT1, CCM2, and PDCD10 are the three loci to date linked to familial CCM development, although germline mutations have also been detected in patients affected by sporadic forms. In this context, the main challenge is to draw up criteria to formulate genotype-phenotype correlations. Clearly, genetic factors determining incomplete penetrance of CCM need to be identified. Here, we report two novel intronic variants probably affecting splicing. Molecular screening of CCM genes was performed on DNA purified by peripheral blood. Coding exons and intron-exon boundaries were sequenced by the Sanger method. The first was detected in a sporadic patient and involves KRIT1. The second affects CCM2 and it is harbored by a woman with familial CCM. Interestingly, molecular analysis extended to both healthy and ill relatives allowed to estimate, for the first time, a penetrance for CCM2 lower than 100%, as to date reported. Moreover, heterogeneity of clinical manifestations among those affected carrying the same genotype further confirms involvement of modifier factors in CCM development. Frontiers Media S.A. 2018-11-14 /pmc/articles/PMC6246743/ /pubmed/30487773 http://dx.doi.org/10.3389/fneur.2018.00953 Text en Copyright © 2018 Scimone, Donato, Katsarou, Bostantjopoulou, D'Angelo and Sidoti. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neurology Scimone, Concetta Donato, Luigi Katsarou, Zoe Bostantjopoulou, Sevasti D'Angelo, Rosalia Sidoti, Antonina Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance |
title | Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance |
title_full | Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance |
title_fullStr | Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance |
title_full_unstemmed | Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance |
title_short | Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance |
title_sort | two novel krit1 and ccm2 mutations in patients affected by cerebral cavernous malformations: new information on ccm2 penetrance |
topic | Neurology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246743/ https://www.ncbi.nlm.nih.gov/pubmed/30487773 http://dx.doi.org/10.3389/fneur.2018.00953 |
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