Alternative titles; symbols
HGNC Approved Gene Symbol: PDCD10
Cytogenetic location: 3q26.1 Genomic coordinates (GRCh38) : 3:167,683,298-167,734,892 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.1 | Cerebral cavernous malformations-3 | 603285 | Autosomal dominant | 3 |
Bergametti et al. (2005) noted that PDCD10 cDNA was originally cloned on the basis of its upregulated expression in the human myeloid cell line TF-1, in which apoptosis was induced by deprivation of granulocyte macrophage colony-stimulating factor (CSF2; 138960), and that PDCD10 cDNA and genomic structures were reported in several genome databases with more than 150 reported ESTs. The coding portion of the cDNA is 636 bp long and encodes a 212-amino acid predicted protein. Three alternative transcripts that differed only in their 5-prime untranslated regions had been identified. Database searches by Bergametti et al. (2005) did not identify any paralog but identified several strongly conserved orthologs both in vertebrate and invertebrate species. Searches of protein databases with the coding sequence of human PDCD10 did not reveal a signal peptide, transmembrane domain, or any known functional domain. Northern blot analysis showed varying levels of a 1.35-kb transcript in all tissues tested, with highest expression in heart, skeletal muscle, and placenta.
The PDCD10 gene extends more than 50 kb and includes 7 coding exons and three 5-prime noncoding exons (Bergametti et al., 2005). The ATG initiator codon is located in the fourth exon.
The implication of the PDCD10 gene in cerebral cavernous malformations strongly suggested that it is a new player in vascular morphogenesis and/or remodeling (Bergametti et al., 2005).
By GST pull-down and coimmunoprecipitation analysis, Voss et al. (2007) demonstrated that CCM2/malcavernin (607929) coprecipitated and colocalized with PDCD10. Yeast 2-hybrid analysis showed that PDCD10 directly bound to STK25 (602255) and the phosphatase domain of FAP1 (600267). PDCD10 was phosphorylated by STK25, whereas the C-terminal domain of FAP1 dephosphorylated PDCD10. Further experiments showed that STK25 and CCM2 formed a protein complex. The findings linked PDCD10 and STK25 with CCM2, which is part of signaling pathways that are essential for vascular development. Voss et al. (2007) hypothesized that PDCD10 is part of the KRIT1 (604214)/CCM2 protein complex through its interaction with CCM2, and therefore may participate in CCM1-dependent modulation of beta-1 integrin (ITGB1; 135630) signaling.
Borikova et al. (2010) showed that knockdown of Ccm1, Ccm2, or Ccm3 in mouse embryonic endothelial cells induced RhoA (165390) overexpression and persistent RhoA activity at the cell edge, as well as in the cytoplasm and nucleus. RhoA activation was especially pronounced following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited formation of vessel-like tubes and invasion of extracellular matrix. Knockdown or inhibition of Rock2 (604002) countered these effects and was associated with inhibition of RhoA-stimulated phosphorylation of myosin light chain-2 (MLC2; see 160781). Borikova et al. (2010) concluded that the CCM protein complex regulates RhoA activation and cytoskeletal dynamics.
Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurologic deficits. Several genetic forms have been identified: 1 form, CCM1 (116860) which maps to 7q, is caused by loss-of-function mutations in the KRIT1 gene. A second form, CCM2 (603284), which maps to 7p, is due to loss-of-function mutations in the CCM2 gene. Bergametti et al. (2005) reported the identification of PDCD10 as the gene mutant in CCM3, which had been mapped to 3q26-q27. Bergametti et al. (2005) hypothesized that genomic deletions might occur at the CCM3 locus, as reported previously to occur at the CCM2 locus. Using high-density microsatellite genotyping of 20 families, they identified, in 1 of these, null alleles that resulted from deletion within an interval overlapping the previously identified linkage mapping interval. They found that PDCD10, which was 1 of 5 known genes mapping within this interval, contained 6 distinct deleterious mutations 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 or CCM2 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 CCM3, Liquori et al. (2008) identified a heterozygous deletion of the entire gene (609118.0007).
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1, CCM2/malcavernin, 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.
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.
Boulday et al. (2011) noted that deletion of Ccm1, Ccm2, or Ccm3 in mice is embryonic lethal. They generated mice with an endothelial-specific Ccm2 deletion at postnatal day 1, which resulted in vascular lesions mimicking human CCM lesions. Deletion of Ccm1 or Ccm3 at postnatal day 1 resulted in similar cerebellar and retinal lesions. Ccm2 lesion development was restricted to the venous bed. Boulday et al. (2011) concluded that the consequences of Ccm2 deletion depend on the developmental timing of the ablation and are associated with a developmental stage with intense angiogenesis.
In 2 families, Bergametti et al. (2005) found that individuals with cerebral cavernous malformations (CCM3; 603285) had a C-to-T transition at nucleotide 586 in exon 10 of the PDCD10 gene, resulting in a stop codon at codon 196. In 1 family the affected individuals were 2 sisters; in the second family mother and daughter were affected.
In a family in which mother and daughter had cerebral cavernous malformations (CCM3; 603285), Bergametti et al. (2005) found that the affected individuals carried a C-to-T transition of nucleotide 385 in exon 7 of the PDCD10 gene, resulting in a stop codon at codon 129.
Bergametti et al. (2005) found that a single individual with cerebral cavernous malformations (CCM3; 603285) had a de novo mutation in exon 5 of the PDCD10 gene: 103C-T, resulting in a stop codon at codon 35.
In a family in which a father and 2 sons had cerebral cavernous malformations (CCM3; 603285), Bergametti et al. (2005) found a 54-bp deletion in the PDCD10 cDNA that removed nucleotides 97 to 150 (97_150del54). The effect of the mutation was deletion of exon 5.
In a family in which the father and a son had cerebral cavernous malformations (CCM3; 603285), Bergametti et al. (2005) found that affected individuals had a 4-bp deletion involving 1 of the 2 AAGT short repeats located between exon 9 and intron 9 of the PDCD10 gene (556_557+2del4) resulting in abnormal splicing of exon 9, leading to a frameshift and a change in the position of the stop codon (TGA, nt637-639/TGA, nt681-683).
In a family with a single case of cerebral cavernous malformations (CCM3; 603285), Bergametti et al. (2005) found that the proband had a de novo splice site mutation in intron 8 of the PDCD10 gene (475-1G-A).
In an Italian patient with cerebral cavernous malformations (CCM3; 603285), Liquori et al. (2008) identified a heterozygous deletion of the entire PDCD10 gene.
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]
Borikova, A. L., Dibble, C. F., Sciaky, N., Welch, C. M., Abell, A. N., Bencharit, S., Johnson, G. L. Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J. Biol. Chem. 285: 11760-11764, 2010. [PubMed: 20181950] [Full Text: https://doi.org/10.1074/jbc.C109.097220]
Boulday, G., Rudini, N., Maddaluno, L., Blecon, A., Arnould, M., Gaudric, A., Chapon, F., Adams, R. H., Dejana, E., Tournier-Lasserve, E. Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J. Exp. Med. 208: 1835-1847, 2011. [PubMed: 21859843] [Full Text: https://doi.org/10.1084/jem.20110571]
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]
Voss, K., Stahl, S., Schleider, E., Ullrich, S., Nickel, J., Mueller, T. D., Felbor, U. CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 8: 249-256, 2007. [PubMed: 17657516] [Full Text: https://doi.org/10.1007/s10048-007-0098-9]