title: Update on Novel CCM Gene Mutations in Patients with Cerebral Cavernous Malformations.
abstract: Cerebral cavernous malformations (CCMs) are lesions affecting brain microvessels. The pathogenesis is not clearly understood. Conventional classification criterion is based on genetics, and thus, familial and sporadic forms can be distinguished; however, classification of sporadic cases with multiple lesions still remains uncertain. To date, three CCM causative genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. In our previous mutation screening, performed in a cohort of 95 Italian patients, with both sporadic and familial cases, we identified several mutations in CCM genes. This study represents further molecular screening in a cohort of 19 Italian patients enrolled by us in the few last years and classified into familial, sporadic and sporadic with multiple lesions cases. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect point mutations and large genomic rearrangements, respectively. Effects of detected mutations and single-nucleotide polymorphisms (SNPs) were evaluated by an in silico approach and by western blot analysis. A novel nonsense mutation in CCM1 and a novel missense mutation in CCM2 were detected; moreover, several CCM2 gene polymorphisms in sporadic CCM patients were reported. We believe that these data enrich the mutation spectrum of CCM genes, which is useful for genetic counselling to identify both familial and sporadic CCM cases, as early as possible.
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.|Department of Cutting-Edge Medicine and Therapies, Biomolecular Strategies and Neuroscience, Section of Neuroscience-applied, Molecular Genetics and Predictive Medicine, I.E.ME.S.T, Palermo, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Scimone
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Alafaci
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Granata
authors.affiliation: Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche Region, Ancona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Piva
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.|Department of Cutting-Edge Medicine and Therapies, Biomolecular Strategies and Neuroscience, Section of Neuroscience-applied, Molecular Genetics and Predictive Medicine, I.E.ME.S.T, Palermo, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Donato
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Greco
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy. asidoti@unime.it.|Department of Cutting-Edge Medicine and Therapies, Biomolecular Strategies and Neuroscience, Section of Neuroscience-applied, Molecular Genetics and Predictive Medicine, I.E.ME.S.T, Palermo, Italy. asidoti@unime.it.
authors.forename: Antonina
authors.initials: A
authors.lastname: Sidoti
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, via C. Valeria 1, 98125, Messina, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: D'Angelo
mesh_terms: D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002648:Child; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D007223:Infant; D000075927:KRIT1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins
keywords: Brain vascular pathology; CCM gene variants; Early diagnosis; Genetic test update; Predictive medicine