Gene Summary

Gene:PDCD10; programmed cell death 10
Aliases: CCM3, TFAR15
Summary:This gene encodes an evolutionarily conserved protein associated with cell apoptosis. The protein interacts with the serine/threonine protein kinase MST4 to modulate the extracellular signal-regulated kinase (ERK) pathway. It also interacts with and is phosphoryated by serine/threonine kinase 25, and is thought to function in a signaling pathway essential for vascular developent. Mutations in this gene are one cause of cerebral cavernous malformations, which are vascular malformations that cause seizures and cerebral hemorrhages. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:programmed cell death protein 10
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Hemangioma, Cavernous, Central Nervous System
  • Brain and CNS Tumours
  • Italy
  • Magnetic Resonance Imaging
  • Genotype
  • PDCD10
  • Apoptosis Regulatory Proteins
  • DNA Mutational Analysis
  • Cell Line
  • Sequence Deletion
  • Signal Transduction
  • Base Sequence
  • Risk Assessment
  • Codon, Nonsense
  • Childhood Cancer
  • Genetic Testing
  • Chromosome 3
  • Messenger RNA
  • Brain
  • Skin Abnormalities
  • RNA Splice Sites
  • Serpins
  • Retina
  • Pedigree
  • Retinal Neoplasms
  • Membrane Proteins
  • Carrier Proteins
  • Exons
  • Microtubule-Associated Proteins
  • Adolescents
  • Phenotype
  • Spain
  • Brain Tumours
  • Risk Factors
  • Hemangioma, Cavernous
  • Brain Tumours
  • Genetic Predisposition
  • Simvastatin
  • Family Health
  • Endothelial Cells
  • Mutation
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PDCD10 (cancer-related)

Draheim KM, Li X, Zhang R, et al.
CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation.
J Cell Biol. 2015; 208(7):987-1001 [PubMed] Article available free on PMC after 30/09/2015 Related Publications
Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an α-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3.

Imada Y, Yuki K, Migita K, et al.
A Japanese pedigree of familial cerebral cavernous malformations--a case report.
Hiroshima J Med Sci. 2014; 63(4):43-8 [PubMed] Related Publications
Familial cerebral cavernous malformations (FCCM) are autosomal-dominant vascular malformations. At present, 3 cerebral cavernous malformation genes (KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3) have been identified. Few genetic analyses of Japanese FCCM have been reported. A Japanese pedigree of 4 patients with FCCM has been reported that includes the genetic analysis of one of the patients. All 4 patients showed multiple lesions in the brain. Surgical removal was performed at our hospital due to enlargement or hemorrhage of the intracranial lesions in a 21-year-old female (Case 1) and a 30-year-old male (Case 2). The histological diagnoses were cavernous malformations. A 62-year-old female (Case 4), the mother of Cases 1, 2, and 3, suffered from intramedullary hemorrhage at T6-7 and surgical removal was performed at another hospital. Only one patient, a 32-year-old female (Case 3), did not show symptoms. The genetic analysis of Case 2 demonstrated heterozygous partial deletions of exons 12-15 of the KRIT1 gene.

Sun X, Luo S, He Y, et al.
Screening of the miRNAs related to breast cancer and identification of its target genes.
Eur J Gynaecol Oncol. 2014; 35(6):696-700 [PubMed] Related Publications
OBJECTIVE: To predict and verify the target genes of the miRNAs related to breast cancer beginning from the miRNA expression profile of human breast cancer.
MATERIALS AND METHODS: The total RNA was extracted from cancer tissues and the corresponding paracancerous tissues of eight breast cancer patients, and then miRNAs were separated. Human breast cancer cell line MDA-MB-231 and the normal mammary epithelial cell line HBL-100 were cultured, and the total RNA was extracted, respectively, with separation of miRNAs. The gene chip technology was used to analyze and detect the miRNAs differentially expressed in tissues and cancer cells. The miRNA expression profile of human breast cancer was obtained through chip scanning and data analysis.
RESULTS: Through dual-luciferase method, it was verified that PDCD4 and PDCD10 were real target genes of miR-21 and miR-200c, respectively.
CONCLUSION: miR-21 and miR-200c are related miRNAs to breast cancer, and they are associated with the occurrence and development of breast cancer.

Fisher OS, Liu W, Zhang R, et al.
Structural basis for the disruption of the cerebral cavernous malformations 2 (CCM2) interaction with Krev interaction trapped 1 (KRIT1) by disease-associated mutations.
J Biol Chem. 2015; 290(5):2842-53 [PubMed] Article available free on PMC after 30/01/2016 Related Publications
Familial cerebral cavernous malformations (CCMs) are predominantly neurovascular lesions and are associated with mutations within the KRIT1, CCM2, and PDCD10 genes. The protein products of KRIT1 and CCM2 (Krev interaction trapped 1 (KRIT1) and cerebral cavernous malformations 2 (CCM2), respectively) directly interact with each other. Disease-associated mutations in KRIT1 and CCM2 mostly result in loss of their protein products, although rare missense point mutations can also occur. From gene sequencing of patients known or suspected to have one or more CCMs, we discover a series of missense point mutations in KRIT1 and CCM2 that result in missense mutations in the CCM2 and KRIT1 proteins. To place these mutations in the context of the molecular level interactions of CCM2 and KRIT1, we map the interaction of KRIT1 and CCM2 and find that the CCM2 phosphotyrosine binding (PTB) domain displays a preference toward the third of the three KRIT1 NPX(Y/F) motifs. We determine the 2.75 Å co-crystal structure of the CCM2 PTB domain with a peptide corresponding to KRIT1(NPX(Y/F)3), revealing a Dab-like PTB fold for CCM2 and its interaction with KRIT1(NPX(Y/F)3). We find that several disease-associated missense mutations in CCM2 have the potential to interrupt the KRIT1-CCM2 interaction by destabilizing the CCM2 PTB domain and that a KRIT1 mutation also disrupts this interaction. We therefore provide new insights into the architecture of CCM2 and how the CCM complex is disrupted in CCM disease.

Gibson CC, Zhu W, Davis CT, et al.
Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation.
Circulation. 2015; 131(3):289-99 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
BACKGROUND: Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans that has no approved nonsurgical treatment. A subset of patients have a hereditary form of the disease due primarily to loss-of-function mutations in KRIT1, CCM2, or PDCD10. We sought to identify known drugs that could be repurposed to treat CCM.
METHODS AND RESULTS: We developed an unbiased screening platform based on both cellular and animal models of loss of function of CCM2. Our discovery strategy consisted of 4 steps: an automated immunofluorescence and machine-learning-based primary screen of structural phenotypes in human endothelial cells deficient in CCM2, a secondary screen of functional changes in endothelial stability in these same cells, a rapid in vivo tertiary screen of dermal microvascular leak in mice lacking endothelial Ccm2, and finally a quaternary screen of CCM lesion burden in these same mice. We screened 2100 known drugs and bioactive compounds and identified 2 candidates, cholecalciferol (vitamin D3) and tempol (a scavenger of superoxide), for further study. Each drug decreased lesion burden in a mouse model of CCM vascular disease by ≈50%.
CONCLUSIONS: By identifying known drugs as potential therapeutics for CCM, we have decreased the time, cost, and risk of bringing treatments to patients. Each drug also prompts additional exploration of biomarkers of CCM disease. We further suggest that the structure-function screening platform presented here may be adapted and scaled to facilitate drug discovery for diverse loss-of-function genetic vascular disease.

Cigoli MS, Avemaria F, De Benedetti S, et al.
PDCD10 gene mutations in multiple cerebral cavernous malformations.
PLoS One. 2014; 9(10):e110438 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

Edelmann AR, Schwartz-Baxter S, Dibble CF, et al.
Systems biology and proteomic analysis of cerebral cavernous malformation.
Expert Rev Proteomics. 2014; 11(3):395-404 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
UNLABELLED: Cerebral cavernous malformations (CCM) are vascular anomalies caused by mutations in genes encoding KRIT1, OSM and PDCD10 proteins causing hemorrhagic stroke. We examine proteomic change of loss of CCM gene expression. Using human umbilical vein endothelial cells, label-free differential protein expression analysis with multidimensional liquid chromatography/tandem mass spectrometry was applied to three CCM protein knockdown cell lines and two control cell lines: ProteomeXchange identifier PXD000362. Principle component and cluster analyses were used to examine the differentially expressed proteins associated with CCM. The results from the five cell lines revealed 290 and 192 differentially expressed proteins (p < 0.005 and p < 0.001, respectively). Most commonly affected proteins were cytoskeleton-associated proteins, in particular myosin-9. Canonical genetic pathway analysis suggests that CCM may be a result of defective cell-cell interaction through dysregulation of cytoskeletal associated proteins.
CONCLUSION: The work explores signaling pathways that may elucidate early detection and novel therapy for CCM.

Zheng X, Riant F, Bergametti F, et al.
Cerebral cavernous malformations arise independent of the heart of glass receptor.
Stroke. 2014; 45(5):1505-9 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
BACKGROUND AND PURPOSE: The Heart of Glass (HEG) receptor binds KRIT1 and functions with KRIT1, CCM2, and PDCD10 in a common signaling pathway required for heart and vascular development. Mutations in KRIT1, CCM2, and PDCD10 also underlie human cerebral cavernous malformation (CCM) and postnatal loss of these genes in the mouse endothelium results in rapid CCM formation. Here, we test the role of HEG in CCM formation in mice and in humans.
METHODS: We constitutively or conditionally deleted Heg and Ccm2 genes in genetically modified mice. Mouse embryos, brain, and retina tissues were analyzed to assess CCM lesion formation.
RESULTS: In postnatal mice, CCMs form with Ccm2-/- but not with Heg-/- or Heg-/-;Ccm2+/- endothelial cells. Consistent with these findings, human patients with CCM who lack exonic mutations in KRIT1, CCM2, or PDCD10 do not have mutations in HEG.
CONCLUSIONS: These findings suggest that the HEG-CCM signaling functions during cardiovascular development and growth, whereas CCMs arise because of loss of HEG-independent CCM signaling in the endothelium of the central nervous system after birth.

Draheim KM, Fisher OS, Boggon TJ, Calderwood DA
Cerebral cavernous malformation proteins at a glance.
J Cell Sci. 2014; 127(Pt 4):701-7 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of current models of CCM protein function focusing on how known protein-protein interactions might contribute to cellular phenotypes and highlighting gaps in our current understanding.

Mondéjar R, Solano F, Rubio R, et al.
Mutation prevalence of cerebral cavernous malformation genes in Spanish patients.
PLoS One. 2014; 9(1):e86286 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
OBJECTIVE: To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients.
METHODS: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing.
RESULTS: A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported.
CONCLUSIONS: Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.

Fisher OS, Boggon TJ
Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology.
Cell Mol Life Sci. 2014; 71(10):1881-92 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms.

Riant F, Odent S, Cecillon M, et al.
Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations.
Clin Genet. 2014; 86(6):585-8 [PubMed] Related Publications
Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.

D'Angelo R, Alafaci C, Scimone C, et al.
Sporadic cerebral cavernous malformations: report of further mutations of CCM genes in 40 Italian patients.
Biomed Res Int. 2013; 2013:459253 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM.

Haghighi A, Fathi D, Shahbazi M, et al.
Identification of a c.601C>G mutation in the CCM1 gene in a kindred with multiple skin, spinal and cerebral cavernous malformations.
J Neurol Sci. 2013; 334(1-2):97-101 [PubMed] Related Publications
Cerebral cavernous malformations (CCM) are congenital vascular anomalies predominantly of the central nervous system but may include lesions in other tissues such as the retina, skin, and liver. These hamartomatous dysplasias, generally occurring sporadically, consist of dynamic clustered convoluted capillary cavities without intervening brain parenchyma that may lead to headaches, seizures, paresis, cerebral hemorrhages and focal neurological deficits. Familial forms of CCM, inherited in an autosomal dominant manner with incomplete penetrance and variable expression, are attributed to mutations in three genes, CCM1, CCM2 and CCM3. Here, we report a kindred of Persian descent exhibiting a range of clinical symptoms and features that include seizures, multiple lesions of the brain and spinal cord, and severe hyperkeratotic cutaneous capillary-venous malformations. Sanger DNA sequencing and deletion/duplication testing of the CCM1, CCM2, and CCM3 genes in the proband revealed a CCM1 c.601C>G mutation. Targeted mutation analysis in family members confirmed that this mutation segregated with the disease in the family. This family illustrates the phenotypic heterogeneity that has been observed in other reported CCM-pedigrees and highlights the importance of genetic testing for early diagnosis in familial CCM. To our knowledge, this is the first genetic investigation of CCM in the Persian population.

Maddaluno L, Rudini N, Cuttano R, et al.
EndMT contributes to the onset and progression of cerebral cavernous malformations.
Nature. 2013; 498(7455):492-6 [PubMed] Related Publications
Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.

Schröder W, Najm J, Spiegler S, et al.
Predictive genetic testing of at-risk relatives requires analysis of all CCM genes after identification of an unclassified CCM1 variant in an individual affected with cerebral cavernous malformations.
Neurosurg Rev. 2014; 37(1):161-5 [PubMed] Related Publications
The mutation detection rate for familial cerebral cavernous malformations (CCM) is extremely high, being about 90 % if direct sequencing of the three genes, CCM1, CCM2, and CCM3, is used in conjunction with quantitative analyses to detect larger CCM1-3 deletions/duplications. We here report on an individual who had presented with more than 30 cerebral and spinal cavernous malformations, two intracranial meningiomas, and disease manifestation only in the mid-forties. A CCM1 missense variant of unclear relevance was found during the first sequencing step. Thereafter, direct sequencing of all three CCM genes revealed the typical pathogenic loss-of-function mutation c.598C > T/p.Q200* in the CCM3 gene. Our results demonstrate that mutation analyses of all three CCM genes in the index patient regardless of previous identification of an unclassified CCM1 variant is crucial for reliable predictive testing of at-risk relatives.

Riant F, Cecillon M, Saugier-Veber P, Tournier-Lasserve E
CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions.
Neurogenetics. 2013; 14(2):133-41 [PubMed] Related Publications
Loss of function mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 gene are identified in about 95 % of familial cases of cerebral cavernous malformations and 2/3 of sporadic cases with multiple lesions. In this study, 279 consecutive index patients referred for either genetic counseling or for diagnosis of cerebral hemorrhage of unknown etiology were analyzed for the three cerebral cavernous malformations (CCM) genes by direct sequencing and quantitative studies, to characterize in more detail the mutation spectrum associated with cerebral cavernous malformations and to optimize CCM gene screening. Analysis of the cDNA was performed when possible to detect the consequences of the genomic variations. A pathogenic mutation was identified in 122 patients. CCM1 was mutated in 80 patients (65 %), CCM2 in 23 (19 %), and CCM3 in 19 (16 %). One hundred patients harbored a loss of function point mutation (82 %) and 22 had a large deletion (18 %). Novel unclassified variants were detected in the patients among whom six led to a splicing defect. The causality of three missense variants that did not modify the splicing could not be established. These findings expand the CCM mutation spectrum and highlight the importance of screening the three CCM genes with both direct sequencing and a quantitative method. In addition, six new unclassified variants were shown to be deleterious because they led to a splicing defect. This underlines the necessity of the cDNA analysis when an unknown variant is detected.

Fischer A, Zalvide J, Faurobert E, et al.
Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis.
Trends Mol Med. 2013; 19(5):302-8 [PubMed] Related Publications
Cerebral cavernous malformations (CCMs) are vascular lesions that can occur sporadically or as a consequence of inherited loss-of-function mutations, predominantly in the genes CCM1 (KRIT1), CCM2 (MGC4607, OSM, Malcavernin), or CCM3 (PDCD10, TFAR15). Inherited, familial CCM is characterized by the development of multiple lesions throughout a patient's life leading to recurrent cerebral hemorrhages. Recently, roles for the CCM proteins in maintaining vascular barrier functions and quiescence have been elucidated, and in this review we summarize the genetics and pathophysiology of this disease and discuss the molecular mechanisms through which CCM proteins may act within blood vessels.

Tsutsumi S, Ogino I, Miyajima M, et al.
Genomic causes of multiple cerebral cavernous malformations in a Japanese population.
J Clin Neurosci. 2013; 20(5):667-9 [PubMed] Related Publications
Cerebral cavernous malformation (CCM) is a hamartomatous vascular disease affecting the central nervous system. A fraction of CCM are thought to arise in association with genomic mutations in the cerebral cavernous malformation 1 (CCM1) (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10) genes. In the present study, 18 Japanese patients with multiple CCM (10 with familial type and eight with sporadic type), underwent genomic analysis for CCM1, CCM2 and CCM3 mutations with blood samples and surgical specimens. MRI showed CCM in the cerebral hemisphere in 17 patients, the cerebellum in 10, the brainstem in 10 and the spinal cord in eight. CCM2 mutations were the most prominent, followed by CCM1 and CCM3. CCM1, CCM2 and CCM3 mutations were not identified in seven patients. Among the 10 patients with familial CCM, CCM1, CCM2 and CCM3 mutations were found in two, three and one patient, respectively, whereas four patients lacked these mutations. Among the eight patients with sporadic CCM, these mutations were found in one, three, and one patients, respectively, whereas three patients lacked these mutations. Most of the patients had a stable course during the follow-up period. Genomic mutations other than CCM1, CCM2 and CCM3 may be frequent in patients with multiple CCM in the Japanese population.

Campione E, Diluvio L, Terrinoni A, et al.
Progressive late-onset of cutaneous angiomatosis as possible sign of cerebral cavernous malformations.
Dermatol Online J. 2013; 19(2):2 [PubMed] Related Publications
BACKGROUND: Cerebral cavernous malformations (CCM) comprise enlarged capillary cavities in the central nervous system, with possible retinal or cutaneous vascular malformations. This condition is associated with CCM1, CCM2, and CCM3 gene mutations.
OBJECTIVE: Cutaneous clinical, histological and cerebral MRI findings, including CCM1, CCM2, and CCM3 gene sequencing, of two unrelated, neurological symptom-free patients who consulted for late-onset of deep multiple cutaneous angiomatoid lesions, are described.
RESULTS: The diagnosis of multiple cutaneous angiomatosis was confirmed and related to CCM as detected by MRI in both cases. Analysis of our patients showed normal nucleotide sequences of the genes proposed.
CONCLUSIONS: A progressive late-onset of multiple, deep cutaneous venous malformations may indicate the need to investigate a potential coexistence of CCM by MRI. Early diagnosis and prompt treatment is required in these patients. The absence of CCM1, CCM2, and CCM3 mutations might indicate that different genes could be involved in the pathogenesis of these late-onset patients. Careful questioning about family history of CCM is important; our first patient's daughter had a history of cerebral cavernoma.

You C, Sandalcioglu IE, Dammann P, et al.
Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations.
J Cell Mol Med. 2013; 17(3):407-18 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
CCM3, a product of the cerebral cavernous malformation 3 or programmed cell death 10 gene (CCM3/PDCD10), is broadly expressed throughout development in both vertebrates and invertebrates. Increasing evidence indicates a crucial role of CCM3 in vascular development and in regulation of angiogenesis and apoptosis. Furthermore, loss of CCM3 causes inherited (familial) cerebral cavernous malformation (CCM), a common brain vascular anomaly involving aberrant angiogenesis. This study focused on signalling pathways underlying the angiogenic functions of CCM3. Silencing CCM3 by siRNA stimulated endothelial proliferation, migration and sprouting accompanied by significant downregulation of the core components of Notch signalling including DLL4, Notch4, HEY2 and HES1 and by activation of VEGF and Erk pathways. Treatment with recombinant DLL4 (rhDLL4) restored DLL4 expression and reversed CCM3-silence-mediated impairment of Notch signalling and reduced the ratio of VEGF-R2 to VEGF-R1 expression. Importantly, restoration of DLL4-Notch signalling entirely rescued the hyper-angiogenic phenotype induced by CCM3 silence. A concomitant loss of CCM3 and the core components of DLL4-Notch signalling were also demonstrated in CCM3-deficient endothelial cells derived from human CCM lesions (CCMEC) and in a CCM3 germline mutation carrier. This study defined DLL4 as a key downstream target of CCM3 in endothelial cells. CCM3/DLL4-Notch pathway serves as an important signalling for endothelial angiogenesis and is potentially implicated in the pathomechanism of human CCMs.

Gingras AR, Liu JJ, Ginsberg MH
Structural basis of the junctional anchorage of the cerebral cavernous malformations complex.
J Cell Biol. 2012; 199(1):39-48 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
The products of genes that cause cerebral cavernous malformations (CCM1/KRIT1, CCM2, and CCM3) physically interact. CCM1/KRIT1 links this complex to endothelial cell (EC) junctions and maintains junctional integrity in part by inhibiting RhoA. Heart of glass (HEG1), a transmembrane protein, associates with KRIT1. In this paper, we show that the KRIT1 band 4.1, ezrin, radixin, and moesin (FERM) domain bound the HEG1 C terminus (K(d) = 1.2 µM) and solved the structure of this assembly. The KRIT1 F1 and F3 subdomain interface formed a hydrophobic groove that binds HEG1(Tyr(1,380)-Phe(1,381)), thus defining a new mode of FERM domain-membrane protein interaction. This structure enabled design of KRIT1(L717,721A), which exhibited a >100-fold reduction in HEG1 affinity. Although well folded and expressed, KRIT1(L717,721A) failed to target to EC junctions or complement the effects of KRIT1 depletion on zebrafish cardiovascular development or Rho kinase activation in EC. These data establish that this novel FERM-membrane protein interaction anchors CCM1/KRIT1 at EC junctions to support cardiovascular development.

D'Angelo R, Scimone C, Calabrò M, et al.
Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: a causative mutation?
Gene. 2013; 519(1):202-7 [PubMed] Related Publications
Cerebral cavernous malformations (CCMs; OMIM 116860) are vascular anomalies mostly located in the central nervous system (CNS) and occasionally within the skin and retina. Main clinical manifestations are seizure, hemorrhage, recurrent headaches, focal neurological deficits and epileptic attacks. The CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression. Familial CCMs were associated with causative mutations in the CCM1 [K-Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. This study reports the identification of a previously undescribed deletion mutation in CCM2 gene exon 5, in an Italian family with multiple cerebral cavernous malformations and epilepsy. Mutation c.502_503delAG results in a frame shift causing a TGA stop codon. This truncates the mutant CCM2 gene protein, the malcavernin, to 233 amino acids, respect to 444 amino acids of the wild-type malcavernin. By using real-time RT-PCR, we have found that the mRNA resulting from two nucleotides deletion showed a 70% reduction relative to the wild-type transcript, indicating that it may be subject to a degradation mechanism such as nonsense-mediated decay (NMD).

Zheng Y, Qiu J, Hu J, Wang G
Concepts and hypothesis: integrin cytoplasmic domain-associated protein-1 (ICAP-1) as a potential player in cerebral cavernous malformation.
J Neurol. 2013; 260(1):10-9 [PubMed] Related Publications
Cerebral cavernous malformation (CCM) is a common vascular disease in central nervous system that frequently predisposes to stroke, seizure, and cerebral hemorrhage. CCM lesions are characterized by dilated and leaky intracranial capillaries composed of a thin layer of vascular endothelial cells with abnormal subendothelial extracellular matrix. Despite the understanding that genetic mutation of three CCM genes (CCM1, CCM2, and CCM3) results in hereditary CCM, the molecular mechanism underlying vascular defects in CCM lesions remains poorly understood. Recent studies have shown that integrin cytoplasmic domain-associated protein-1 (ICAP-1, also known as integrin β1 binding protein1, ITGB1BP), a cytoplasmic protein interacting with both β1 integrin subunit and CCM1 protein (also known as Krit1), is implicated in vascular development. Analysis of data on the biochemistry and cellular biology of ICAP-1 highlights that bidirectional interaction of ICAP-1 with CCM1 and integrin might regulate diverse pathological processes of CCM disorder. Specifically, emerging evidence supports the hypothesized involvement of ICAP-1 in CCM pathogenesis through its significant effect in attenuating excessive vascular growth, its indispensable function in activating CCM1 protein, and its essential role in regulating integrin functions.

Kivelev J, Niemelä M, Hernesniemi J
Characteristics of cavernomas of the brain and spine.
J Clin Neurosci. 2012; 19(5):643-8 [PubMed] Related Publications
The incidence of cavernomas in the general population ranges from 0.3% to 0.5%. They frequently occur in young adults, usually being detected between the second and fifth decade of life, in both sporadic and familial forms. Patients with inherited cavernomas are typically affected by multiple lesions, whereas sporadic forms mostly present with a single lesion. Three genes responsible for development of cavernomas identified to date include CCM1, CCM2, and CCM3. The natural history of brain cavernomas is relatively benign and up to 21% of patients are asymptomatic. The most frequent manifestations of the disease are seizures, focal neurological deficits, and hemorrhage. We review the current literature data on the characteristics of brain and spinal cavernomas.

Mosca L, Pileggi S, Avemaria F, et al.
De novo MGC4607 gene heterozygous missense variants in a child with multiple cerebral cavernous malformations.
J Mol Neurosci. 2012; 47(3):475-80 [PubMed] Related Publications
Cavernous malformations are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics; main clinical manifestations are seizure, focal neurological deficits and epileptic attacks. Here we describe the molecular characterization of an Italian child, a symptomatic patient, affected by multiple cerebral cavernous malformations, without a family history of the disease and harbouring a new MGC4607 gene mutation. We identified two de novo missense variants in exon 6 of the gene both present on the same allele (cis configuration). DNA analysis for KRIT1, and PDCD10 gene variation through direct sequencing and MLPA analysis excluded further mutations. STR multiplex assay, allele-specific analysis and DHPLC analysis were performed for a better genetic characterization. Our findings emphasize the importance of the genetic test in subjects presenting multiple cerebral cavernomas for an adequate counselling, as well as for disease management since early identification of genetic abnormalities enable patients to have their lesions removed before they haemorrhage and cause deficit and/or epilepsy.

D'Angelo R, Scimone C, Rinaldi C, et al.
CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study.
Int J Mol Med. 2012; 29(6):1113-20 [PubMed] Related Publications
Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Among our group of CCM Italian patients, we selected a cohort of sporadic cases negative for mutations in CCM genes. In this cohort, five variants in CCM2 gene were detected, which proved to be the known polymorphisms in intronic regions (IVS2-36A>G and IVS8 +119 C>T) and in coding sequence (c.157 G>A in exon 2, c.358 G>A in exon 4 and c.915 G>A in exon 8). Therefore, we undertook a case-control study to investigate the possible association of these polymorphisms with sporadic CCMs. The five polymorphisms were identified in 91 CCM sporadic patients and in 100 healthy controls by direct sequencing methods using lymphocyte DNA. Polymorphisms IVS2-36A>G and c.915 G>A showed statistically significant differences in frequencies between patients and controls [(χ2, 6.583; P<0.037); (χ2, 14.205; P<0.001)]. The prevalence of the wild-type genotype was significantly lower in the CCM group than in the control sample. Patients with the A/G and G/G genotypes (IVS2-36A>G) had a significant increase for CCM risk (OR, 3.08; 95% CI, 1.5-5.9 and OR, 4.3; 95% CI, 1.4-22.6) and the same was observed for the polymorphism c.915 G> A (genotype G/A OR, 6.1; 95% CI, 3.0-12.6 and genotype A/A OR, 2.79). In addition, the polymorphisms c.358 G>A in exon 4 (χ2, 15.977; P<0.04) and c.915 G>A in exon 8 (χ2, 18.109; P<0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 G>A (p.Val120Ile), c.915 G>A (p.Thr305 Thr) and IVS2-36A>G, shows that haplotype GAG (+--) significantly increased among CCM sporadic patients compared to the control group. Significant differences between patients and controls were observed only for IVS2-36A>G and c.915 G>A polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 G>A and c.915 G>A were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.

Cunningham K, Uchida Y, O'Donnell E, et al.
Conditional deletion of Ccm2 causes hemorrhage in the adult brain: a mouse model of human cerebral cavernous malformations.
Hum Mol Genet. 2011; 20(16):3198-206 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
Cerebral cavernous malformations (CCM) are irregularly shaped and enlarged capillaries in the brain that are prone to hemorrhage, resulting in headaches, seizures, strokes and even death in patients. The disease affects up to 0.5% of the population and the inherited form has been linked to mutations in one of three genetic loci, CCM1, CCM2 and CCM3. To understand the pathophysiology underlying the vascular lesions in CCM, it is critical to develop a reproducible mouse genetic model of this disease. Here, we report that limited conditional ablation of Ccm2 in young adult mice induces observable neurological dysfunction and reproducibly results in brain hemorrhages whose appearance is highly reminiscent of the lesions observed in human CCM patients. We first demonstrate that conventional or endothelial-specific deletion of Ccm2 leads to fatal cardiovascular defects during embryogenesis, including insufficient vascular lumen formation as well as defective arteriogenesis and heart malformation. These findings confirm and extend prior studies. We then demonstrate that the inducible deletion of Ccm2 in adult mice recapitulates the CCM-like brain lesions in humans; the lesions display disrupted vascular lumens, enlarged capillary cavities, loss of proper neuro-vascular associations and an inflammatory reaction. The CCM lesions also exhibit damaged neuronal architecture, the likely cause of neurologic defects, such as ataxia and seizure. These mice represent the first CCM2 animal model for CCM and should provide the means to elucidate disease mechanisms and evaluate therapeutic strategies for human CCM.

Tanriover G, Sozen B, Gunel M, Demir N
CCM2 expression during prenatal development and adult human neocortex.
Int J Dev Neurosci. 2011; 29(5):509-14 [PubMed] Related Publications
Cerebral cavernous malformation (CCM) is one of the most common types of vascular malformations of the central nervous system, affecting nearly one in 200 people. CCM lesions are characterized by grossly dilated vascular channels lined by a single layer of endothelium. Genetic linkage analyses have mapped three CCM loci to CCM1, CCM2 and CCM3. All three causative genes have now been identified allowing new insights into CCM pathophysiology. We focused on the CCM2 protein that might take place in blood vessel formation; we report here the expression patterns of CCM2 in prenatal development and adult human neocortex by means of immunohistochemistry and Western blot analysis. CCM2 was obviously detected in vascular endothelium and neuroglial precursor cells during development and also observed in arterial endothelium, neurons, some of the glial cells in adult neocortex. The expression patterns suggest that it could be one of the arterial markers whether this is a cause or a consequence of an altered vascular identity. CCM2 might play a role during vasculogenesis and angiogenesis during human brain development. Furthermore, with this study, CCM2 have been described for the first time in developing human neocortex.

Chan AC, Drakos SG, Ruiz OE, et al.
Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice.
J Clin Invest. 2011; 121(5):1871-81 [PubMed] Article available free on PMC after 20/01/2016 Related Publications
Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krev1 interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Krit1. PDCD10 bound to germinal center kinase III (GCKIII) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcd10 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity.

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