Mondéjar, RufinoSolano, FranciscaRubio, RocíoDelgado, MercedesPérez-Sempere, AngelGonzález-Meneses, AntonioVendrell, TeresaIzquierdo, GuillermoMartinez-Mir, AmaliaLucas, Miguel2015-01-202015-01-202014-01-23Mondéjar R, Solano F, Rubio R, Delgado M, Pérez-Sempere A, González-Meneses A, et al. Mutation prevalence of cerebral cavernous malformation genes in Spanish patients. PLoS ONE.2014, 9(1):e86286http://hdl.handle.net/10668/1790Journal Article; Research Support, Non-U.S. Gov't;OBJECTIVE To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients. METHODS We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing. RESULTS A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported. CONCLUSIONS Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.enProteínas reguladoras de la apoptosisSecuencia de basesProteínas transportadorasAnálisis de mutaciones del ADNHemangioma cavernoso del sistema nervioso centralProteínas protooncogénicasMedical Subject Headings::Named Groups::Persons::Age Groups::AdultMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::AgedMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Aged::Aged, 80 and overMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Apoptosis Regulatory ProteinsMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base SequenceMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier ProteinsMedical Subject Headings::Named Groups::Persons::Age Groups::ChildMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger::Codon::Codon, Terminator::Codon, NonsenseMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational AnalysisMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Gene FrequencyMedical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Nervous System Malformations::Central Nervous System Vascular Malformations::Hemangioma, Cavernous, Central Nervous SystemMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane ProteinsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Cytoskeletal Proteins::Microtubule Proteins::Microtubule-Associated ProteinsMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single NucleotideMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::PrevalenceMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Oncogene Proteins::Proto-Oncogene ProteinsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Mutagenesis::Sequence DeletionMedical Subject Headings::Geographicals::Geographic Locations::Europe::SpainMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young AdultMedical Subject Headings::Named Groups::Persons::Age Groups::Adolescentresearch article24466005open access10.1371/journal.pone.00862861932-6203PMC3900513