RT Journal Article
T1 Mutation prevalence of cerebral cavernous malformation genes in Spanish patients.
A1 Mondéjar, Rufino
A1 Solano, Francisca
A1 Rubio, Rocío
A1 Delgado, Mercedes
A1 Pérez-Sempere, Angel
A1 González-Meneses, Antonio
A1 Vendrell, Teresa
A1 Izquierdo, Guillermo
A1 Martinez-Mir, Amalia
A1 Lucas, Miguel
K1 Proteínas reguladoras de la apoptosis
K1 Secuencia de bases
K1 Proteínas transportadoras
K1 Análisis de mutaciones del ADN
K1 Hemangioma cavernoso del sistema nervioso central
K1 Proteínas protooncogénicas
AB OBJECTIVETo study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients.METHODSWe 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.RESULTSA 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.CONCLUSIONSAnalysis 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.
PB Public Library of Science
YR 2014
FD 2014-01-23
LK http://hdl.handle.net/10668/1790
UL http://hdl.handle.net/10668/1790
LA en
NO Mondéjar 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):e86286
NO Journal Article; Research Support, Non-U.S. Gov't;
DS RISalud
RD Apr 19, 2025