Research Article| Volume 334, ISSUE 1-2, P97-101, November 15, 2013

Identification of a c.601C>G mutation in the CCM1 gene in a kindred with multiple skin, spinal and cerebral cavernous malformations

  • Author Footnotes
    1 The first two authors should be considered as joint first authors.
    Alireza Haghighi
    Corresponding author at: Department of Genetics and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
    1 The first two authors should be considered as joint first authors.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women’s Hospital, USA

    Department of Genetics, Harvard Medical School, USA
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  • Author Footnotes
    1 The first two authors should be considered as joint first authors.
    Davood Fathi
    1 The first two authors should be considered as joint first authors.
    Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran

    International Neuroscience Institute, Hannover, Germany

    Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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  • Majid Shahbazi
    Medical Cellular & Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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  • Mohammad-Mahdy Motahari
    Department of Ophthalmology, Golestan University of Medical Sciences, Gorgan, Iran
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  • Bethany Friedman
    GeneDx, Gaithersburg, MD, USA
    Search for articles by this author
  • Author Footnotes
    1 The first two authors should be considered as joint first authors.
Published:September 05, 2013DOI:


      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.


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        • Rigamonti D.
        • Drayer B.P.
        • Johnson P.C.
        • Hadley M.N.
        • Zabramski J.
        • Spetzler R.F.
        The MRI appearance of cavernous malformations (angiomas).
        J Neurosurg. Oct 1987; 67 ([PubMed PMID: 3655889. Epub 1987/10/01. eng.]): 518-524
        • Zabramski J.M.
        • Wascher T.M.
        • Spetzler R.F.
        • Johnson B.
        • Golfinos J.
        • Drayer B.P.
        • et al.
        The natural history of familial cavernous malformations: results of an ongoing study.
        J Neurosurg. Mar 1994; 80 ([PubMed PMID: 8113854. Epub 1994/03/01. eng.]): 422-432
        • Brunereau L.
        • Levy C.
        • Laberge S.
        • Houtteville J.
        • Labauge P.
        De novo lesions in familial form of cerebral cavernous malformations: clinical and MR features in 29 non-Hispanic families.
        Surg Neurol. May 2000; 53 ([discussion 82-3. PubMed PMID: 10874147. Epub 2000/06/30. eng.]): 475-482
        • Zabramski J.M.
        • Henn J.S.
        • Coons S.
        Pathology of cerebral vascular malformations.
        Neurosurg Clin N Am. Jul 1999; 10 ([PubMed PMID: 10419567. Epub 1999/07/27. eng.]): 395-410
        • Dobyns W.B.
        • Michels V.V.
        • Groover R.V.
        • Mokri B.
        • Trautmann J.C.
        • Forbes G.S.
        • et al.
        Familial cavernous malformations of the central nervous system and retina.
        Ann Neurol. Jun 1987; 21 ([PubMed PMID: 3606045. Epub 1987/06/01. eng.]): 578-583
        • Labauge P.
        • Enjolras O.
        • Bonerandi J.J.
        • Laberge S.
        • Dandurand M.
        • Joujoux J.M.
        • et al.
        An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families.
        Ann Neurol. Feb 1999; 45 ([PubMed PMID: 9989629. Epub 1999/02/16. eng.]): 250-254
        • Eerola I.
        • Plate K.H.
        • Spiegel R.
        • Boon L.M.
        • Mulliken J.B.
        • Vikkula M.
        KRIT1 is mutated in hyperkeratotic cutaneous capillary–venous malformation associated with cerebral capillary malformation.
        Hum Mol Genet. May 22 2000; 9 ([PubMed PMID: 10814716. Epub 2000/05/18. eng.]): 1351-1355
        • Chen D.H.
        • Lipe H.P.
        • Qin Z.
        • Bird T.D.
        Cerebral cavernous malformation: novel mutation in a Chinese family and evidence for heterogeneity.
        J Neurol Sci. Apr 15 2002; 196 ([PubMed PMID: 11959162. Epub 2002/04/18. eng.]): 91-96
        • Ardeshiri A.
        • Beiras-Fernandez A.
        • Steinlein O.K.
        • Winkler P.A.
        Multiple cerebral cavernous malformations associated with extracranial mesenchymal anomalies.
        Neurosurg Rev. Jan 2008; 31 ([discussion 7–8. PubMed PMID: 17957396. Epub 2007/10/25. eng.]): 11-17
        • Denier C.
        • Labauge P.
        • Bergametti F.
        • Marchelli F.
        • Riant F.
        • Arnoult M.
        • et al.
        Genotype–phenotype correlations in cerebral cavernous malformations patients.
        Ann Neurol. Nov 2006; 60 ([PubMed PMID: 17041941. Epub 2006/10/17. eng.]): 550-556
        • Cavalcanti D.D.
        • Kalani M.Y.
        • Martirosyan N.L.
        • Eales J.
        • Spetzler R.F.
        • Preul M.C.
        Cerebral cavernous malformations: from genes to proteins to disease.
        J Neurosurg. Sep 30 2011; 116 ([PubMed PMID: 21962164. Epub 2011/10/04. Eng.]): 122-132
        • Stockton R.A.
        • Shenkar R.
        • Awad I.A.
        • Ginsberg M.H.
        Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity.
        J Exp Med. Apr 12 2010; 207 ([PubMed PMID: 20308363. Pubmed Central PMCID: 2856024. Epub 2010/03/24. eng.]): 881-896
        • Verlaan D.J.
        • Siegel A.M.
        • Rouleau G.A.
        Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.
        Am J Hum Genet. Jun 2002; 70 ([PubMed PMID: 11941540. Pubmed Central PMCID: 379143. Epub 2002/04/10. eng.]): 1564-1567
        • Battistini S.
        • Rocchi R.
        • Cerase A.
        • Citterio A.
        • Tassi L.
        • Lando G.
        • et al.
        Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation.
        Arch Neurol. Jun 2007; 64 ([PubMed PMID: 17562932. Epub 2007/06/15. eng.]): 843-848
        • Toldo I.
        • Drigo P.
        • Mammi I.
        • Marini V.
        • Carollo C.
        Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation.
        Surg Neurol. Feb 2009; 71 ([PubMed PMID: 18207546. Epub 2008/01/22. eng.]): 167-171
        • Verlaan D.J.
        • Davenport W.J.
        • Stefan H.
        • Sure U.
        • Siegel A.M.
        • Rouleau G.A.
        Cerebral cavernous malformations: mutations in Krit1.
        Neurology. 2002; 58: 853-857
        • Sirvente J.
        • Enjolras O.
        • Wassef M.
        • Tournier-Lasserve E.
        • Labauge P.
        Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations.
        J Eur Acad Dermatol Venereol. Sep 2009; 23 ([PubMed PMID: 19453802. Epub 2009/05/21. eng.]): 1066-1072
        • Felbor U.
        • Sure U.
        • Grimm T.
        • Bertalanffy H.
        Genetics of cerebral cavernous angioma.
        Zentralbl Neurochir. 2006; 67: 110-116
        • Surucu O.
        • Sure U.
        • Gaetzner S.
        • Stahl S.
        • Benes L.
        • Bertalanffy H.
        • et al.
        Clinical impact of CCM mutation detection in familial cavernous angioma.
        Childs Nerv Syst. 2006; 22: 1461-1464
        • Labauge P.
        • Laberge S.
        • Brunereau L.
        • Levy C.
        • Tournier-Lasserve E.
        Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Societe Francaise de Neurochirurgie.
        Lancet. Dec 12 1998; 352 ([PubMed PMID: 9863787. Epub 1998/12/24. eng.]): 1892-1897