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

Published online by Cambridge University Press:  16 December 2016

Nicolas Dupré*
Affiliation:
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
Dominique J. Verlaan
Affiliation:
Center for Research in Neurosciences, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
Collette K. Hand
Affiliation:
Center for Research in Neurosciences, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
Sandra B. Laurent
Affiliation:
Center for Research in Neurosciences, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
Gustavo Turecki
Affiliation:
Douglas Hospital Research Institute, Department of Psychiatry, McGill University, Verdun, Quebec, Canada
W. Jeptha Davenport
Affiliation:
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
Nicola Acciarri
Affiliation:
Neurosurgical Department, Bellaria Hospital, Via Altura, Italy
Johannes Dichgans
Affiliation:
Department of Neurology, University of Tübingen, Tübingen, Germany
Akio Ohkuma
Affiliation:
Department of Neurosurgery, Gifu Prefectural Hospital, Gifu City, Japan
Adrian M. Siegel
Affiliation:
Epilepsy Program, Department of Neurology, University Hospital Zürich, Zürich, Switzerland
Guy A. Rouleau
Affiliation:
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
*
Center for Research in Neurosciences, Montreal General Hospital and Department of Neurology and Neurosurgery, McGill University, 1650 Cedar Ave., Montreal, Quebec, H3G 1A4 Canada
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Abstract:

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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

RÉSUMÉContexte:

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.

Type
Original Article
Copyright
Copyright © The Canadian Journal of Neurological 2003

References

REFERENCES

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.Google Scholar
2. De Curling, O, Kelly, DL, Elster, AD, Craven, TE. An analysis of the natural history of cavernous angiomas. J Neurosurg 1991;75:702708.Google Scholar
3. Maraire, N, Awad, IA. Intracranial cavernous malformations: lesion behavior and management strategies. Neurosurgery 1995;37:591605.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
5. Russel, DS, Rubenstein, LJ. Pathology of tumors of the nervous system. Baltimore, MD: Williams and Wilkins, 1989:730736.Google Scholar
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.Google Scholar
7. Rigamonti, D1, Hadley, MN, Drayer, BP, et al. Cerebral cavernous malformations. New Engl J Med 1988;319:343347.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
9. Gunel, M, Awad, IA, Finberg, K, et al. Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 1996;38:12651271.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
13. Verlaan, DJ, Davenport, WJ, Stefan, H, et al. Literature review and identification of new mutations in the Krit1 gene. Neurology 2002;58:853857.Google Scholar
14. Davenport, WJ, Siegel, AM, Dichgans, J, et al. CCM1 gene mutations in families segregating cerebral cavernous malformations. Neurology 2001;56:540543.Google Scholar
15. Cottingham, RWJ, Idury, RM, Schaffer, AA. Faster sequential genetic linkage computation. Am J Hum Genet 1993;53:252263.Google Scholar
16. Schaffer, AA, Gupta, SK, Schriram, K, Cottingham, RWJ. Avoiding recomputation in linkage analysis. Hum Hered 1994;44:225237.Google ScholarPubMed
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.Google Scholar
18. Ott, J. Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 1989;86:41754178.CrossRefGoogle ScholarPubMed
19. Weeks, DE, Lathrop, GM. SLINK: a general simulation program for linkage analysis. Am J Hum Genet 1990;(Suppl 47):A204.Google Scholar
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.Google Scholar
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.Google Scholar