Journal of Molecular Neuroscience

, Volume 57, Issue 3, pp 400–403 | Cite as

Detection of Novel Mutation in Ccm3 Causes Familial Cerebral Cavernous Malformations

  • Concetta Scimone
  • Placido Bramanti
  • Alessia Ruggeri
  • Zoe Katsarou
  • Luigi Donato
  • Antonina SidotiEmail author
  • Rosalia D’Angelo


Cerebral cavernous malformations are vascular lesions that usually involve brain micro-vessels. They can occur both in a sporadic form and familial one. Causes of familial forms are mutations at three loci: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. Here, we describe a novel CCM3 missense mutation (c.422T>G) detected in two Greek brothers showing multiple lesions at magnetic resonance imaging; to date, only the youngest is symptomatic. Bioinformatics tools showed this novel variant causes a loss of function in Pdcd10 protein due to its localization in the eighth helix and, particularly, affects Leu141, a highly conserved amino acid. Roles of Pdcd10 in angiogenesis regulation and its association with early development of cerebral cavernous malformations were also considered.


Familial cerebral cavernous malformations CCM3 mutation Incomplete penetrance Impaired angiogenesis 



We are thankful to Dr. Eugenia Avdellidou and Dr. Eleni Fourkala of the Department of Neurology, Hippokration General Hospital, Thessaloniki, Greece, for their contribution to this study.


  1. Bacigaluppi S, Retta SF, Pileggi S, Fontanella M, Goitre L, Tassi L, La Camera A, Citterio A, Patrosso MC, Tredici G, Penco S (2013) Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management. Clin Genet 83(1):7–14CrossRefPubMedGoogle Scholar
  2. Chen DL, Wang ZW, Ren C, Zeng ZL, Wang DS, Luo HY, Wang F, Qiu MZ, Bai L, Zhang DS, Wang FH, Li YH, Xu RH (2013) Abnormal expression of paxillin correlates with tumor progression and poor survival in patients with gastric cancer. J Transl Med 11:277PubMedCentralCrossRefPubMedGoogle Scholar
  3. D’Angelo R, Scimone C, Rinaldi C, Trimarchi G, Italiano D, Bramanti P, Amato A, Sidoti A (2012) CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study. Int J Mol Med 29(6):1113–1120PubMedGoogle Scholar
  4. Felbor U, Sure U, Grimm T, Bertalanffy H (2006) Genetics of cerebral cavernous angioma. Zentralbl Neurochir 67(3):110–116CrossRefPubMedGoogle Scholar
  5. Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013) Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med 19(5):302–308CrossRefPubMedGoogle Scholar
  6. Goudreault M, D’Ambrosio LM, Kean MJ, Mullin MJ, Larsen BG, Sanchez A, Chaudhry S, Chen GI, Sicheri F, Nesvizhskii AI, Aebersold R, Raught B, Gingras AC (2009) A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Mol Cell Proteomics 8(1):157–171PubMedCentralCrossRefPubMedGoogle Scholar
  7. Guazzi P, Goitre L, Ferro E, Cutano V, Martino C, Trabalzini L, Retta SF (2012) Identification of the Kelch family protein Nd1-L as a novel molecular interactor of KRIT1. PLoS One 7(9), e44705PubMedCentralCrossRefPubMedGoogle Scholar
  8. Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ (2012) Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. Eur J Hum Genet 20(2):134–140PubMedCentralCrossRefPubMedGoogle Scholar
  9. He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal 3(116):ra26PubMedCentralCrossRefPubMedGoogle Scholar
  10. Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6(3):237–244CrossRefPubMedGoogle Scholar
  11. Lee KS, Spetzler RF (1989) Cerebral cavernous malformations. Arch Neurol 46(12):1273CrossRefPubMedGoogle Scholar
  12. Li X, Zhang R, Zhang H, He Y, Ji W, Min W, Boggon TJ (2010) Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem 285(31):24099–24107PubMedCentralCrossRefPubMedGoogle Scholar
  13. Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, Marcondes de Souza J, Lee C, Marchuk DA, Awad IA (2014) Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med 17(3):188–196CrossRefPubMedGoogle Scholar
  14. Uhlik MT, Abell AN, Johnson NL, Sun W, Cuevas BD, Lobel-Rice KE, Horne EA, Dell’Acqua ML, Johnson GL (2003) Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 5(12):1104–1110CrossRefPubMedGoogle Scholar
  15. Voss K, Stahl S, Schleider E, Ullrich S, Nickel J, Mueller TD, Felbor U (2007) CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 8(4):249–256CrossRefPubMedGoogle Scholar
  16. You C, Sandalcioglu IE, Dammann P, Felbor U, Sure U, Zhu Y (2013) Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. J Cell Mol Med 17(3):407–418PubMedCentralCrossRefPubMedGoogle Scholar
  17. Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, Marchuk DA (2005) CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 14(17):2521–2531CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Concetta Scimone
    • 1
  • Placido Bramanti
    • 2
  • Alessia Ruggeri
    • 1
  • Zoe Katsarou
    • 3
  • Luigi Donato
    • 1
  • Antonina Sidoti
    • 1
    Email author
  • Rosalia D’Angelo
    • 1
  1. 1.Department of Biomedical Sciences and Morpho-functional Images, Division of Medical Biotechnologies and Preventive MedicineUniversity of MessinaMessinaItaly
  2. 2.IRCCS Centro Neurolesi “Bonino-Pulejo”MessinaItaly
  3. 3.Department of NeurologyHippokration General HospitalThessalonikiGreece

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