title: Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: a causative mutation?
abstract: Cerebral cavernous malformations (CCMs; OMIM 116860) are vascular anomalies mostly located in the central nervous system (CNS) and occasionally within the skin and retina. Main clinical manifestations are seizure, hemorrhage, recurrent headaches, focal neurological deficits and epileptic attacks. The CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression. Familial CCMs were associated with causative mutations in the CCM1 [K-Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. This study reports the identification of a previously undescribed deletion mutation in CCM2 gene exon 5, in an Italian family with multiple cerebral cavernous malformations and epilepsy. Mutation c.502_503delAG results in a frame shift causing a TGA stop codon. This truncates the mutant CCM2 gene protein, the malcavernin, to 233 amino acids, respect to 444 amino acids of the wild-type malcavernin. By using real-time RT-PCR, we have found that the mRNA resulting from two nucleotides deletion showed a 70% reduction relative to the wild-type transcript, indicating that it may be subject to a degradation mechanism such as nonsense-mediated decay (NMD).
authors.affiliation: Department of Biomorphology and Biotechnologies, Division of Biology and Genetics, Faculty of Medicine, University of Messina, via C. Valeria 1, I-98125 Messina, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: D'Angelo
authors.forename: Concetta
authors.initials: C
authors.lastname: Scimone
authors.forename: Marco
authors.initials: M
authors.lastname: Calabrò
authors.forename: Carla
authors.initials: C
authors.lastname: Schettino
authors.forename: Mario
authors.initials: M
authors.lastname: Fratta
authors.forename: Antonina
authors.initials: A
authors.lastname: Sidoti
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics*; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D044465:White People / Q000235:genetics*
chemical_list: C502544:CCM2 protein, human; D002352:Carrier Proteins; D012333:RNA, Messenger