title: Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations.
abstract: Cerebral Cavernous Malformations (CCM/MIM 604214) are vascular malformations characterised by abnormally enlarged capillary cavities without intervening brain parenchyma. Clinical manifestations include seizures, cerebral haemorrhages and focal neurological deficits. They occur as a sporadic or autosomal dominant condition. Most often, sporadic cases have only one lesion and familial cases are characterised by a high frequency of multiple lesions. Three CCM loci were previously mapped on 7q (CCM1), 7p (CCM2) and 3q (CCM3) and CCM1 gene was identified as coding Krit1, a protein of unknown function, which was shown initially to interact in yeast two hybrid assays with Rap1A, a small ras GTPase and more recently to Icap1alpha, a modulator of beta1 integrin signal transduction. Herein, we screened KRIT1 gene in 121 unrelated, consecutively recruited, CCM probands having at least one affected relative and/or showing multiple lesions on cerebral MRI. Fifty-two of these probands (43%) were shown to carry a KRIT1 mutation. Forty-two distinct mutations were identified including six recurrent ones. Three-quarters of these mutations were located in the C-terminal half of the gene, mostly within exons 13, 15 and 17. All of them are predicted to lead to a premature stop codon. No missense mutation was identified. The only two nucleotide substitutions predicted to be missense mutations led in fact to an abnormal splicing and a premature stop codon. Altogether these data suggest that KRIT1 mRNA decay due to the presence of premature stop codons and Krit1 haploinsufficiency may be the underlying mechanism of CCM.
authors.affiliation: INSERM EMI 99-21, Faculté de Médecine Lariboisière, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Cavé-Riant
authors.forename: Christian
authors.initials: C
authors.lastname: Denier
authors.forename: Pierre
authors.initials: P
authors.lastname: Labauge
authors.forename: Michaelle
authors.initials: M
authors.lastname: Cécillon
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Maciazek
authors.forename: Anne
authors.initials: A
authors.lastname: Joutel
authors.forename: Sophie
authors.initials: S
authors.lastname: Laberge-Le Couteulx
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D005260:Female; D015894:Genome, Human; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins