title: Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene.
abstract: BACKGROUND
  Cerebral cavernous malformations (CCM) present as either sporadic or autosomal dominant conditions with incomplete penetrance of symptoms. Differences in genetic and environmental factors might be minimized among first-degree relatives. We therefore studied clinical expression in a family with several affected members.
  
  
  METHODS
  We studied a three-generation family with the onset of CCM as a cerebral haemorrhage in the younger (four-year-old) sibling. Identification and enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the whole brains. Genetic analysis comprised SCCP, sequencing and restriction polymorphism of the Krit1 gene in the proband and at risk relatives.
  
  
  RESULTS
  The phenotypes of cerebral cavernous malformations (CCMs) in carriers of Krit1 mutations were very variable. We identified a novel frameshift mutation caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a premature TAA triplet and predicts the truncating phenotype Y634X. A very striking finding was the absence of both clinical symptoms and CCMs in the eldest sibling harbouring the 1902insA.
  
  
  CONCLUSIONS
  Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation. The early and critical onset in the proband contrasts with minor clinical findings in affected relatives. This consideration is important in genetic counselling.
authors.affiliation: Molecular Biology Services of the Virgen Macarena University Hospital, Avda Dr, Fedriani sn, 41009 Sevilla, Spain. lucas@us.es
authors.forename: Miguel
authors.initials: M
authors.lastname: Lucas
authors.forename: Alzenire F
authors.initials: AF
authors.lastname: Costa
authors.forename: José M
authors.initials: JM
authors.lastname: García-Moreno
authors.forename: Francisca
authors.initials: F
authors.lastname: Solano
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gamero
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
mesh_terms: D002543:Cerebral Hemorrhage / Q000175:diagnosis / Q000235:genetics; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D006239:Haplotypes; D020786:Hemangioma, Cavernous, Central Nervous System / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins