Mutation prevalence of cerebral cavernous malformation genes in Spanish patients

PLoS One. 2014 Jan 23;9(1):e86286. doi: 10.1371/journal.pone.0086286. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis Regulatory Proteins / genetics*
  • Base Sequence
  • Carrier Proteins / genetics*
  • Child
  • Codon, Nonsense
  • DNA Mutational Analysis
  • Gene Frequency
  • Hemangioma, Cavernous, Central Nervous System / epidemiology
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Humans
  • KRIT1 Protein
  • Membrane Proteins / genetics*
  • Microtubule-Associated Proteins / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Proto-Oncogene Proteins / genetics*
  • Sequence Deletion
  • Spain
  • Young Adult


  • Apoptosis Regulatory Proteins
  • CCM2 protein, human
  • Carrier Proteins
  • Codon, Nonsense
  • KRIT1 Protein
  • KRIT1 protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • PDCD10 protein, human
  • Proto-Oncogene Proteins

Grants and funding

This work has been supported by grants CP10/00526 (Instituto de Salud Carlos III, Spain) and P07-CVI-02790 (Junta de Andalucía, Spain). RM received a fellowship of José Luis Castaño Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.