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 Icap1α, a modulator of β1 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.
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Acknowledgements
We thank the families for their participation; all members of the Société Française de Neurochirurgie who participated in this study. C Denier is a recipient of a fellowship from Poste Accueil INSERM. S Laberge-le Couteulx benefited from a studentship from Fonds de Recherche en Santé du Québec and Fondations (1996-99) pour la Recherche Médicale (1999-00). This work was supported by INSERM, AFM, Fondation de France, Ministère Français de la Recherche.
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Cavé-Riant, F., Denier, C., Labauge, P. et al. Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations. Eur J Hum Genet 10, 733–740 (2002). https://doi.org/10.1038/sj.ejhg.5200870
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DOI: https://doi.org/10.1038/sj.ejhg.5200870
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