Denier et al. (2006) compared the clinical features of mutation carriers from 86 families with CCM1, 25 families with CCM2 (603284), and 17 families with CCM3, ascertained from academic medical centers in France. Of the 3 groups, CCM3 ... Denier et al. (2006) compared the clinical features of mutation carriers from 86 families with CCM1, 25 families with CCM2 (603284), and 17 families with CCM3, ascertained from academic medical centers in France. Of the 3 groups, CCM3 families had the lowest number of affected individuals per family, and the highest proportion of patients with onset of symptoms before age 15 years. Cerebral hemorrhage was the most common initial presentation in patients with CCM3.
Bergametti et al. (2005) reported the identification of the PDCD10 gene (609118) as the CCM3 gene. The CCM3 locus had been mapped to 3q26-q27 within a 22-cM interval bracketed by D3S1763 and D3S1262. They hypothesized that genomic deletions ... Bergametti et al. (2005) reported the identification of the PDCD10 gene (609118) as the CCM3 gene. The CCM3 locus had been mapped to 3q26-q27 within a 22-cM interval bracketed by D3S1763 and D3S1262. They hypothesized that genomic deletions might occur at the CCM3 locus as had been reported at the CCM2 locus. Therefore, through high-density microsatellite genotyping of 20 families, they identified, in 1 family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and D3S1614. This de novo deletion encompassed D3S1763, which strongly suggested that the CCM3 gene lay within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional distinct deleterious mutations within PDCD10, 1 of the 5 known genes mapped within this interval, were identified in 7 families. Three of these mutations were nonsense mutations, and 2 led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the 6 mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes. By screening 8 exons of the PDCD10 gene, Verlaan et al. (2005) identified 2 different heterozygous mutations in 2 of 15 unrelated families with CCM that did not have mutations in the KRIT1 (604214) or CCM2 (607929) genes. The findings suggested that mutations in the PDCD10 gene account for only a small percentage of CCM families and that there is likely another causative gene. In an Italian patient with CCM, Liquori et al. (2008) identified heterozygosity for complete deletion of the CCM3 gene (609118.0007). Through repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, Akers et al. (2009) identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. Akers et al. (2009) suggested that CCM lesion genesis may require complete loss of function for 1 of the CCM genes.