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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
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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

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.

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

References

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