ORPHA: 221061; DO: 0060671;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q26.1 | Cerebral cavernous malformations-3 | 603285 | Autosomal dominant | 3 | PDCD10 | 609118 |
A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-3 (CCM3) is caused by heterozygous mutation in the PDCD10 gene (609118) on chromosome 3q26.
Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM3 pathogenesis, see PATHOGENESIS and MOLECULAR GENETICS sections.
For a phenotypic description and a discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860).
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.
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1 (604214), CCM2/malcavernin (607929), or PDCD10 protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient, normal brain endothelium from a CCM2 patient, and capillary endothelial cells of vessels in a revascularized thrombosed cavern from a CCM3 patient stained positively for KRIT1, CCM2/malcavernin, and PDCD10 respectively. Pagenstecher et al. (2009) suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation.
Among Hispanic Americans, virtually all cerebral cavernous malformation (CCM) is attributable to a founder mutation localized to 7q (CCM1; 116860). Craig et al. (1998) reported analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. Linkage to new loci, CCM2 at 7p15-p13 and CCM3 at 3q25.2-q27, was demonstrated. Multilocus analysis yielded a maximum lod score of 14.11, with 14% of kindreds linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3, with highly significant evidence for linkage to 3 loci; linkage to 3 loci was supported with an odds ratio of 2.6 x 10(5):1 over linkage to 2 loci, and 1.6 x 10(9):1 over linkage to 1 locus. Multipoint analysis among families with high posterior probabilities of linkage to each of the 3 loci refined the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these 3 loci can account for inheritance of CCM in all kindreds studied. Significant locus-specific differences in penetrance were identified.
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 one of the CCM genes.
Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum. Molec. Genet. 18: 919-930, 2009. [PubMed: 19088123] [Full Text: https://doi.org/10.1093/hmg/ddn430]
Bergametti, F., Denier, C., Labauge, P., Arnoult, M., Boetto, S., Clanet, M., Coubes, P., Echenne, B., Ibrahim, R., Irthum, B., Jacquet, G., Lonjon, M., Moreau, J. J., Neau, J. P., Parker, F., Tremoulet, M., Tournier-Lasserve, E., Societe Francaise de Neurochirurgie. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am. J. Hum. Genet. 76: 42-51, 2005. [PubMed: 15543491] [Full Text: https://doi.org/10.1086/426952]
Craig, H. D., Gunel, M., Cepeda, O., Johnson, E. W., Ptacek, L., Steinberg, G. K., Ogilvy, C. S., Berg, M. J., Crawford, S. C., Scott, R. M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C. T. C., Mettler, G., Beis, M. J., Fryer, A., Awad, I. A., Lifton, R. P. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Molec. Genet. 7: 1851-1858, 1998. [PubMed: 9811928] [Full Text: https://doi.org/10.1093/hmg/7.12.1851]
Denier, C., Labauge, P., Bergametti, F., Marchelli, F., Riant, F., Arnoult, M., Maciazek, J., Vicaut, E., Brunereau, L., Tournier-Lasserve, E., Societe Francaise de Neurochirurgie. Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann. Neurol. 60: 550-556, 2006. [PubMed: 17041941] [Full Text: https://doi.org/10.1002/ana.20947]
Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F. Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9: 25-31, 2008. [PubMed: 18060436] [Full Text: https://doi.org/10.1007/s10048-007-0109-x]
Pagenstecher, A., Stahl, S., Sure, U., Felbor, U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Molec. Genet. 18: 911-918, 2009. [PubMed: 19088124] [Full Text: https://doi.org/10.1093/hmg/ddn420]
Verlaan, D. J., Roussel, J., Laurent, S. B., Elger, C. E., Siegel, A. M., Rouleau, G. A. CCM3 mutations are uncommon in cerebral cavernous malformations. Neurology 65: 1982-1983, 2005. [PubMed: 16380626] [Full Text: https://doi.org/10.1212/01.wnl.0000188903.75144.49]