Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9302235 Publication Model: Print Cited Medium: Print ISSN: 1018-4813 (Print) Linking ISSN: 10184813 NLM ISO Abbreviation: Eur J Hum Genet Subsets: MEDLINE

Publication: <2003->: London : Nature Publishing Group
Original Publication: Basel ; New York : Karger, [1992-

Mutation*; Hemangioma, Cavernous, Central Nervous System/*genetics ; Microtubule-Associated Proteins/*genetics ; Proto-Oncogene Proteins/*genetics; DNA Mutational Analysis ; DNA, Complementary ; Female ; Genome, Human ; Humans ; KRIT1 Protein ; Male ; Polymorphism, Genetic ; RNA Splicing/genetics

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.

0 (DNA, Complementary)
0 (KRIT1 Protein)
0 (KRIT1 protein, human)
0 (Microtubule-Associated Proteins)
0 (Proto-Oncogene Proteins)

Date Created: 20021031 Date Completed: 20030610 Latest Revision: 20171116

20221213

10.1038/sj.ejhg.5200870

12404106