Update on Novel CCM Gene Mutations in Patients with Cerebral Cavernous Malformations
- 403 Downloads
Cerebral cavernous malformations (CCMs) are lesions affecting brain microvessels. The pathogenesis is not clearly understood. Conventional classification criterion is based on genetics, and thus, familial and sporadic forms can be distinguished; however, classification of sporadic cases with multiple lesions still remains uncertain. To date, three CCM causative genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. In our previous mutation screening, performed in a cohort of 95 Italian patients, with both sporadic and familial cases, we identified several mutations in CCM genes. This study represents further molecular screening in a cohort of 19 Italian patients enrolled by us in the few last years and classified into familial, sporadic and sporadic with multiple lesions cases. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect point mutations and large genomic rearrangements, respectively. Effects of detected mutations and single-nucleotide polymorphisms (SNPs) were evaluated by an in silico approach and by western blot analysis. A novel nonsense mutation in CCM1 and a novel missense mutation in CCM2 were detected; moreover, several CCM2 gene polymorphisms in sporadic CCM patients were reported. We believe that these data enrich the mutation spectrum of CCM genes, which is useful for genetic counselling to identify both familial and sporadic CCM cases, as early as possible.
KeywordsBrain vascular pathology CCM gene variants Early diagnosis Genetic test update Predictive medicine
Compliance with Ethical Standards
DNA blood samples were obtained with written informed consent from all patients and normal controls. For underage patients, consent was obtained from the parents. Study protocol followed the guidelines of the local ethics committee, and the investigation was conducted with the ethical requirements defined in the Helsinki Declaration.
Conflict of Interest
The authors declare that they have no conflicts of interest.
- Bravi L, Malinverno M, Pisati F, Rudini N, Cuttano R, Pallini R, Martini M, Larocca LM, Locatelli M, Levi V, Bertani GA, Dejana E, Lampugnani MG (2016) Endothelial cells lining sporadic cerebral cavernous malformation cavernomas undergo endothelial-to-mesenchymal transition. Stroke 47:886–890PubMedGoogle Scholar
- Craig HD, Günel M, Cepeda O, Johnson EW, Ptacek L, Steinberg GK, Ogilvy CS, Berg MJ, Crawford SC, Scott RM, Steichen-Gersdorf E, Sabroe R, Kennedy CT, Mettler G, Beis MJ, Fryer A, Awad IA, Lifton RP (1998) Multilocus linkage identifies two new loci for a Mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 7:1851–1858CrossRefPubMedGoogle Scholar
- D’Angelo R, Marini V, Rinaldi C, Origone P, Dorcaratto A, Avolio M, Goitre L, Forni M, Capra V, Alafaci C, Mareni C, Garrè C, Bramanti P, Sidoti A, Retta SF, Amato A (2011) Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation. Brain Pathol 21:215–224CrossRefPubMedGoogle Scholar
- D’Angelo R, Alafaci C, Scimone C, Ruggeri A, Salpietro FM, Bramanti P, Tomasello F, Sidoti A (2013) Sporadic cerebral cavernous malformations: report of further mutations of CCM genes in 40 Italian patients. Biomed Res Int 459253Google Scholar
- Fidalgo M, Guerrero A, Fraile M, Iglesias C, Pombo CM, Zalvide J (2012) Adaptor protein cerebral cavernous malformation 3 (CCM3) mediates phosphorylation of the cytoskeletal proteins ezrin/radixin/moesin by mammalian Ste20-4 to protect cells from oxidative stress. J Biol Chem 287:11556–11565CrossRefPubMedPubMedCentralGoogle Scholar
- Harel L, Costa B, Tcherpakov M, Zapatka M, Oberthuer A, Hansford LM, Vojvodic M, Levy Z, Chen ZY, Lee FS, Avigad S, Yaniv I, Shi L, Eils R, Fischer M, Brors B, Kaplan DR, Fainzilber M (2009) CCM2 mediates death signaling by the TrkA receptor tyrosine kinase. Neuron 63:585–591CrossRefPubMedGoogle Scholar
- Notelet L, Chapon F, Khoury S, Vahedi K, Chodkiewicz JP, Courtheoux P, Iba-Zizen MT, Cabanis EA, Lechevalier B, Tournier-Lasserve E, Houtteville JP (1997) Familial cavernous malformations in a large French kindred: mapping of the gene to the CCM1 locus on chromosome 7q. J Neurol Neurosurg Psychiatry 63:40–45CrossRefPubMedPubMedCentralGoogle Scholar
- Spiegler S, Najm J, Liu J, Gkalympoudis S, Schröder W, Borck G, Brockmann K, Elbracht M, Fauth C, Ferbert A, Freudenberg L, Grasshoff U, Hellenbroich Y, Henn W, Hoffjan S, Hüning I, Korenke GC, Kroisel PM, Kunstmann E, Mair M, Munk-Schulenburg S, Nikoubashman O, Pauli S, Rudnik-Schöneborn S, Sudholt I, Sure U, Tinschert S, Wiednig M, Zoll B, Ginsberg MH, Felbor U (2014) High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors. Mol Genet Genomic Med 2:176–185CrossRefPubMedPubMedCentralGoogle Scholar