Linkage to the CCM2 locus and genetic heterogeneity in familial cerebral cavernous malformation.
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.
Dupré
Nicolas
N
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Verlaan
Dominique J
DJ
Hand
Collette K
CK
Laurent
Sandra B
SB
Turecki
Gustavo
G
Davenport
W Jeptha
WJ
Acciarri
Nicola
N
Dichgans
Johannes
J
Ohkuma
Akio
A
Siegel
Adrian M
AM
Rouleau
Guy A
GA
D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D020786:Hemangioma, Cavernous, Central Nervous System / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
D005819:Genetic Markers; D008780:Methyltransferases; C055097:mRNA (guanine(N7))-methyltransferase