title: Detection of the founder effect in Finnish CADASIL families.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. kati.mykkanen@utu.fi
authors.forename: Kati
authors.initials: K
authors.lastname: Mykkänen
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Savontaus
authors.forename: Vesa
authors.initials: V
authors.lastname: Juvonen
authors.forename: Pertti
authors.initials: P
authors.lastname: Sistonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Tuisku
authors.forename: Susanna
authors.initials: S
authors.lastname: Tuominen
authors.forename: Maila
authors.initials: M
authors.lastname: Penttinen
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
authors.forename: Matti
authors.initials: M
authors.lastname: Viitanen
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Minna
authors.initials: M
authors.lastname: Pöyhönen
mesh_terms: 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
chemical_list: C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D001120:Arginine; D003545:Cysteine