Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지

Family Linkage Analysis of CCM1 Locus on Chromosome 7q in Familial Cavernous Malformation

가족성 해면혈관종에서 염색체 7q CCM1 염기서열의 가족간 연관성 분석

  • Sim Ki-Bum (Department of Neurosurgery, College of Medicine, Cheju National University) ;
  • Lee Chang Sub (Department of Neurosurgery, College of Medicine, Cheju National University) ;
  • Kim Seung-Ki (Division of Pediatric Neurosurgery and Clinical Research Institute, Seoul National University Children's Hospital) ;
  • Wang Kyu-Chang (Division of Pediatric Neurosurgery and Clinical Research Institute, Seoul National University Children's Hospital) ;
  • Kim Young-Im (Neuroscience Research Institute, SNUMRC) ;
  • Cho Byung-Kyu (Division of Pediatric Neurosurgery and Clinical Research Institute, Seoul National University Children's Hospital)
  • 심기범 (제주대학교 의과대학 신경외과학교실) ;
  • 이창섭 (제주대학교 의과대학 신경외과학교실) ;
  • 김승기 (서울대학교 어린이병원 신경외과학 교실) ;
  • 왕규창 (서울대학교 어린이병원 신경외과학 교실) ;
  • 김영임 (서울대학교 의학연구원 신경과학연구소) ;
  • 조병규 (서울대학교 어린이병원 신경외과학 교실)
  • Published : 2005.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

Although the pathogenesis of cerebral cavernous malformation (CCM) is unknown, a familial predisposition has been recognized, with up to $55\%$ of patients having an affected relatives. Genetic linkage studies have recently mapped a gene causing CCM to a segment of the long arm of chromosome 7 (7q). We report herein a genetic linkage analysis conducted on a Korean three generation family with CCM. It's first report in Korean family. A Korean family in which one member had undergone surgery for ubtracerebrak hematoma (ICH) and confirmed the CCM, was evaluated. They were examined clinically (n=18) and by magnetic resonance (MR) imaging (n=10). Polymorphic markers (D7S1813, D7S1789) spanning the CCM1 locus on 7q were genotyped by the polymerase chain reaction and analysis of linkage was performed in this family (n=17). Six had multiple lesions on brain MR image, one of them being symptomatic, and five were asymptomatic. Seven remaining members were asymptomatic and refused MR image study. One had died of ICH from presumed CCM. Analysis of the pedigree was consistent with an autosomal dominant pattern of inheritance. All affected patients were linked to CCM1. Linkage to CCM1 can account for inheritance of CCM in this family. They had some striking features with a low clinical penetrance and the presence of multiple lesions. These findings have implications for genetic testing of this disorder and represent an important step toward identification of the gene responsible for the pathogenesis of this disease.

Keywords

References

  1. Brunereau, L., Labauge, P., Tournier-Lasserve, E., Laberge, S., Levy, C. and Houtteville, J.P. (2000): Familial form of intracranial cavernous angioma: MR imaging findings in 51 families. Radiology, 214, 209-216 https://doi.org/10.1148/radiology.214.1.r00ja19209
  2. Causse, M.A., Fulton, T.M., Cho, Y.G., Ahn, S.N., Cung-wongse, J., Wu, K., Xiao, J., Yu, Z., Ronald, P.C., Harrington, S.E., Second, G., McCauch, S.R. and Tanksley, S.D. (1994): Saturated molecular map of the rice genome based on an interspecific backcross population. Genetics, 138, 1251-1274
  3. Chen, D.H., Lipe, H.P., Qin, Z. and Bird, T.D. (2002): Cerebral cavernous malformation: novel mutation in a Chinese family and evidence for heterogeneity. J. Neurol. Sci., 196, 91-96 https://doi.org/10.1016/S0022-510X(02)00031-X
  4. Craig, H.D., Gunel, M., Cepeda, O., Johnson, E.W., Ptacek, L., Steinberg, G.K., Ogilvy, C.S., Berg, M.J., Crawford, S.C., Scott, R.M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C.T., Mettler, G., Beis, M.J., Fryer, A., Awad, I.A. and Lifton, R.P. (1998): Multilocus linkage identifies two new loci for a mendel ian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Mol. Genet., 7, 1851-1858 https://doi.org/10.1093/hmg/7.12.1851
  5. Davenport, W.J., Siegel, A.M., Dichgans, J., Drigo, P, Mammi, I., Pereda, P., Wood, N.W and Rouleau, GA (2001): CCM1 gene mutations in families segregating cerebral cavernous malformations. Neurology, 56, 540-543 https://doi.org/10.1212/WNL.56.4.540
  6. Dubovsky, J., Zabramski, J.M., Kurth, J., Spettzler, R.F., Rich, S.S., Orr, H.T. and Weber, J.L. (1995): A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum. Mol. Genet., 4, 453-458 https://doi.org/10.1093/hmg/4.3.453
  7. Dupre, N., Verlaan, D.J., Hand, C.K., Laurent, S.B., Turecki, G., Davenport, W.J., Acciarri, N., Dichgans, J., Ohkuma, A. and Siegel, A.M. (2003): Linkage to the CCM2 locus and genetic heterogeneity in familial cerebral cavernous malformation. Can. J. Neurol. Sci., 30, 122-128 https://doi.org/10.1017/S0317167100053385
  8. Fobe, J.L., de Lima, J.B., de Buone, M.L. and Correa, Neto. (1996): Familial cavernous angioma. Report in 3 generations. Arq. Neuropsiquiart. (Portugeses), 54, 655-660 https://doi.org/10.1590/S0004-282X1996000400016
  9. Gil-Nagel, A., Dubovsky, J., Wilcox, K.J., Stewart, J.M., Anderson, V.E., Leppik, I.E., Orr, H.T., Johnson, E.W., Weber, J.L. and Rich, S.S. (1996): Familial cerebral cavernous angioma: an autosomal dominant gene localized to a 15 cM interval on human chromosome 7q. Ann. Neurol., 39, 807-810 https://doi.org/10.1002/ana.410390619
  10. Gunel, M., Awad, I.A., Finberg, K., Steinberg, G.K., Craig, H.D. and Cepeda, O. (1996): Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery, 38, 1265-1271 https://doi.org/10.1097/00006123-199606000-00059
  11. Gustincich, S., Manfioletti, G., Del Sal, G., Schneider, C. and Carninici, P. (1991): A fast method for high-quality genomic DNA extraction from whole human blood. Biotechnique, 11, 298-300
  12. Johnson, E.W., Marchuk, D.A. and Zabramski, J.M. (2002): The Genetic of Cerebral Cavernous Malformations. In: Winn HR, Youmans Neruological Surgery 5th ed. Vol 2. Philadelphia: W.B. Saunders, 2299-2304
  13. Kufs, H. (1928): Uber heredofamiliare angiomatose des gehirns und der retina, ihre beziehungen zueinander und zur angiomaose der haul. Z. Neurol. Pyschol., 113, 651-686
  14. Labauge, P., Enjolras, O., Bonerandi, J.J., Laberge, S., Dandurand, M., Joujoux, J.M. and Tournier-Lasserve, E (1999): An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann. Neurol., 45, 250-254 https://doi.org/10.1002/1531-8249(199902)45:2<250::AID-ANA17>3.0.CO;2-V
  15. Laurans, M.S., DiLuna, M.L., Shin, D., Niazi, F., Voorhees, J.R., Nelson-Williams, C., Johnson, E.W., Siegel, A.M., Steinberg, G.K., Berg, M.J., Scott, R.M., Tedeschi, G., Enevoldson, T.P., Anson, J., Rouleau, G.A., Ogilvy, C., Awad, I.A., Lifton, R.P. and Gunel, M. (2003): Mutational analysis of 206 families with cavernous malformations. J. Neurosurg., 99, 38-43 https://doi.org/10.3171/jns.2003.99.1.0038
  16. Louis, D.N., Deimling, A.V. and Seizinger, B.R. (1992): Short communication; a (CA)n dinucleotide repeat assay for evaluating loss of allelic heterozygosity in small and archival human brain tumor specimens. Am. J. Pathol., 141, 777-782
  17. Mason, I., Aase, J.M., Orrison, W.W., Wicks, J.D., Seigel, R.S. and Bicknell, J.M. (1988): Familial cavernous angiomas of the brain in an Hispanic family. Neurology, 38, 324-326 https://doi.org/10.1212/WNL.38.2.324
  18. Moriarity, J.L., Wetzel, M., Clatterbuck, R.E., Javedan, S., Sheppard, J.M., Hoenig-Rigamonti, K., Crone, N.E., Breiter, S.N. and Lee, R.R. (1999): The natural history of cavernous malformations: a prospective study of 68 patients. J. Neurosurg., 44, 1166-1171 https://doi.org/10.1097/00006123-199906000-00003
  19. Notelet, L., Chapon, F., Khoury, S., Vahedi, K., Chodkiewicz, J.P., Courtheoux, P., Iba-Zizen, M.T., Cabanis, E.A., Lechevalier, B., Tournier-Lasserve, E. and Houtteville, J.P. (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, 40-43 https://doi.org/10.1136/jnnp.63.1.40
  20. Ott, J. (1999): Analysis of Human Genetic Linkage, 3rd ed. Baltimore and London: The Johns Hopkins University Press
  21. Polymeropoulos, M.H., Hurko, O., Hsu, F., Rubenstein, J., Basnet, S., Lane, K., Dietz, H., Spetzler, R.F. and Rigamonti, D. (1997): Linkage of the locus for cerebral hemangiomas to human chromosome 7q in four families of Mexican-American descent. Neurology, 48, 752-757 https://doi.org/10.1212/WNL.48.3.752
  22. Reich, P., Winkler, J., Straube, A., Steiger, H.J. and Peraud, A. (2003): Molecular genetic investigations in the CCM1 gene in sporadic cerebral cavernomas. Neurology, 60, 1135-1138 https://doi.org/10.1212/01.WNL.0000055470.62265.44
  23. Rigamonti, D., Hadley, M.N., Drayer, B.P., Johnson, P.C., Hoenig-Rigamonti, K., Knight, J.T. and Spetzler, R.F. (1988): Cerebral cavernous malformations: incidence and familial occurrence. N. Engl. J. Med., 319, 343-347 https://doi.org/10.1056/NEJM198808113190605
  24. Sahoo, T., Goenaga-Diaz, E., Serebriiskii, I.G., Thomas, J.W., Kotova, E., Cuellar, J.G., Peloquin, J.M., Golemis, E., Beitinjaneh, F., Green, E.D., Johnson, E.W. and Marchuk, D.A. (2001): Computational and experimental analyses reveal previously undetected coding exons of the Krit1 (CCM1) gene. Genomics, 71, 123-126 https://doi.org/10.1006/geno.2000.6426
  25. Verlaan, D.J., Davenport, W.J., Stefan, H., Sure, U., Siegel, A.M. and Rouleau, G.A. (2002): Cerebral cavernous malformations: Mutations in Krit1. Neurology, 58, 853-837 https://doi.org/10.1212/WNL.58.6.853
  26. Zabramski, J.M., Wascher, T.M., Spetzler, R.F., Johnson, B., Golfinos, J., Drayer, B.P., Brown, B., Rigamonti, D. and Brown, G.(1994): The natural history of familial cavernous malformations: results of an ongoing study. J. Neurosurg., 80, 422-432 https://doi.org/10.3171/jns.1994.80.3.0422