Detection of the founder effect in Finnish CADASIL families.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by brain infarcts, cognitive decline and dementia. The disease is caused by at least 91 missense mutations, four deletions and one splice site mutation in the NOTCH3 gene, which maps to 19p13.1. In 18 out of the 21 Finnish CADASIL families so far identified, the causative mutation is an arginine to cysteine substitution in position 133 (R133C). Most of the families carrying this mutation originate from the western coast of Finland, thus suggesting a founder effect. No previous reports of a founder effect in CADASIL have been published. We haplotyped 60 patients from these 18 families for 10 microsatellite markers in order to determine whether the families descend from a common ancestor. We found a similar haplotype linked to the mutation in all 18 pedigrees, which indicates a single common ancestor for all the Finnish R133C families. The age analysis of the founder mutation places the introduction of the mutation in the late 1600s or early 1700s.
Mykkänen
Kati
K
Department of Medical Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. kati.mykkanen@utu.fi
Savontaus
Marja-Liisa
ML
Juvonen
Vesa
V
Sistonen
Pertti
P
Tuisku
Seppo
S
Tuominen
Susanna
S
Penttinen
Maila
M
Lundkvist
Johan
J
Viitanen
Matti
M
Kalimo
Hannu
H
Pöyhönen
Minna
M
D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D046589:CADASIL / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D005260:Female; D005387:Finland; D018703:Founder Effect; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface / Q000235:genetics*; D051880:Receptors, Notch
C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D001120:Arginine; D003545:Cysteine