Skip to main content Accessibility help
×
Home

Linkage to the CCM2 Locus and Genetic Heterogeneity in Familial Cerebral Cavernous Malformation

  • Nicolas Dupré (a1), Dominique J. Verlaan (a2), Collette K. Hand (a2), Sandra B. Laurent (a2), Gustavo Turecki (a3), W. Jeptha Davenport (a1), Nicola Acciarri (a4), Johannes Dichgans (a5), Akio Ohkuma (a6), Adrian M. Siegel (a7) and Guy A. Rouleau (a1)...

Abstract:

Background:

Cerebral cavernous malformation (CCM) is a form of intracranial vascular disease that may arise sporadically or be dominantly inherited. Linkage studies have revealed genetic heterogeneity among the dominantly inherited forms suggesting the existence of at least three loci called CCM1, CCM2 and CCM3.

Methods:

In the present study, we screened five families with dominantly inherited CCM for CCM1 gene mutations with denaturing high performance liquid chromatography (DHPLC). Then, we performed linkage analysis and haplotyping on these five families using highly polymorphic markers at the candidate CCM loci.

Results:

None of the five families tested with DHPLC were found to have mutations in the CCM1 gene. Based on haplotyping, we identified three families segregating alleles for CCM2, while two families segregated alleles for CCM3. Using linkage analysis, we could confirm that one family (IFCAS-1) had a positive Lod score of 2.03 (p<0.0001) at the CCM2 locus using marker D7S678.

Conclusions:

The present study is the first one to replicate linkage at the CCM2 locus and provides a fifth family identified as such. It also supports the concept of genetic heterogeneity in CCM, identifying four other families that showed no mutations in the CCM1 gene.

RÉSUMÉ Contexte:

La malformation caverneuse cérébrale (CCM) est une forme de maladie vasculaire intracrânienne qui survient de façon sporadique mais qui peut aussi avoir un mode d'hérédité dominant. Des analyses de liaison ont montré une hétérogénéité génétique parmi les formes dont l'hérédité est dominante, suggérant l'existence d'au moins trois locus, CCM1, CCM2 et CCM3.

Méthodes:

Dans cette étude, nous avons évalué cinq familles présentant une CCM à hérédité dominante pour déterminer la présence de mutations dans le gène CCM1 au moyen de la chromatographie en phase liquide à haute performance dénaturante. Nous avons ensuite procédé à une analyse de liaison et à un haplotypage dans ces cinq familles au moyen de marqueurs très polymorphes des gènes candidats CCM.

Résultats:

Aucune mutation dans le gène CCM1 n'a été démontrée dans les cinq familles étudiées au moyen de marqueurs très polymorphes. Nous avons identifié par haplotypage trois familles où il y a ségrégation d'allèles de CCM2 avec la maladie et deux familles où il y a ségrégation d'allèles de CCM3 avec la maladie. Nous avons confirmé au moyen de l'analyse de liaison, qu'une famille avait un Lod score positif de 2,03 (p<0,0001) au locus CCM2 en utilisant le marqueur D7S678.

Conclusions:

Cette étude est la première à reproduire une liaison au locus CCM2 et identifie une cinquième famille dans laquelle la maladie est liée à ce gène. Elle supporte également le concept d'une hétérogénéité génétique dans la CCM en identifiant quatre autres familles où on n'a pas décelé de mutation dans le gène CCM1.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Linkage to the CCM2 Locus and Genetic Heterogeneity in Familial Cerebral Cavernous Malformation
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Linkage to the CCM2 Locus and Genetic Heterogeneity in Familial Cerebral Cavernous Malformation
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Linkage to the CCM2 Locus and Genetic Heterogeneity in Familial Cerebral Cavernous Malformation
      Available formats
      ×

Copyright

Corresponding author

Center for Research in Neurosciences, Montreal General Hospital and Department of Neurology and Neurosurgery, McGill University, 1650 Cedar Ave., Montreal, Quebec, H3G 1A4 Canada

References

Hide All
1. Otten, P Pizzolato, GP, Rilliet, B, Berney, J. 131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies. Neurochirurgie 1989;35:8283.
2. De Curling, O, Kelly, DL, Elster, AD, Craven, TE. An analysis of the natural history of cavernous angiomas. J Neurosurg 1991;75:702708.
3. Maraire, N, Awad, IA. Intracranial cavernous malformations: lesion behavior and management strategies. Neurosurgery 1995;37:591605.
4. Siegel, AM, Roberts, DW, Harbaugh, RI, Williamson, PD. Purelesionectomy versus tailored epilepsy surgery in treatment of cavernous angioma presenting with epilepsy. Neurosurg Rev 2000;23:8083.
5. Russel, DS, Rubenstein, LJ. Pathology of tumors of the nervous system. Baltimore, MD: Williams and Wilkins, 1989:730736.
6. Perl, J, Ross, J. Diagnostic imaging of cavernous malformations. In: Awad, IA, Barrow, D, (Eds.) Cavernous malformations. Park Ridge, IL: American Association of Neurological Surgeons Press, 1993:3748.
7. Rigamonti, D1, Hadley, MN, Drayer, BP, et al. Cerebral cavernous malformations. New Engl J Med 1988;319:343347.
8. Gunel, M, Awad, IA, Finberg, K, et al. A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. New Engl J Med 1996;334:946951.
9. Gunel, M, Awad, IA, Finberg, K, et al. Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 1996;38:12651271.
10. Craig, HD, Gunel, M, Cepeda, O, et al. 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 1998;7:18511858.
11. Laberge-le Couteulx, S, Jung, HH, Labauge, P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999;23:189193.
12. Siegel, AM, Andermann, E, Badhwar, A, et al. Anticipation in familial cavernous angioma: a study of 52 families from International Familial Cavernous Angioma Study. IFCAS Group. Lancet 1998;352:16761677.
13. Verlaan, DJ, Davenport, WJ, Stefan, H, et al. Literature review and identification of new mutations in the Krit1 gene. Neurology 2002;58:853857.
14. Davenport, WJ, Siegel, AM, Dichgans, J, et al. CCM1 gene mutations in families segregating cerebral cavernous malformations. Neurology 2001;56:540543.
15. Cottingham, RWJ, Idury, RM, Schaffer, AA. Faster sequential genetic linkage computation. Am J Hum Genet 1993;53:252263.
16. Schaffer, AA, Gupta, SK, Schriram, K, Cottingham, RWJ. Avoiding recomputation in linkage analysis. Hum Hered 1994;44:225237.
17. Dubovsky, J, Zabramski, JM, Kurth, J, et al. A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995;4:453458.
18. Ott, J. Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 1989;86:41754178.
19. Weeks, DE, Lathrop, GM. SLINK: a general simulation program for linkage analysis. Am J Hum Genet 1990;(Suppl 47):A204.
20. O’Donovan, MC, Oefner, PJ, Roberts, SC, et al. Blind analysis of denaturing high-performance liquid chromatography as a tool for mutation detection. Genomics 1998;52:4449.
21. Laberge, S, Labauge, P, Marechal, E, et al. Genetic heterogeneity and absence of founder effect in a series of 36 French cerebral cavernous angiomas families. Eur J Hum Genet 1999;7:499504.

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed