Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene

BMC Neurol. 2003 Jul 23;3:5. doi: 10.1186/1471-2377-3-5. Epub 2003 Jul 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebral Hemorrhage / diagnosis
  • Cerebral Hemorrhage / genetics
  • Child, Preschool
  • Codon, Nonsense*
  • DNA Mutational Analysis
  • Haplotypes
  • Hemangioma, Cavernous, Central Nervous System / diagnosis
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Heterozygote*
  • Humans
  • KRIT1 Protein
  • Magnetic Resonance Imaging
  • Microtubule-Associated Proteins / genetics*
  • Pedigree
  • Penetrance*
  • Phenotype
  • Proto-Oncogene Proteins / genetics*
  • Sequence Deletion


  • Codon, Nonsense
  • KRIT1 Protein
  • KRIT1 protein, human
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins