title: Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations.
abstract: Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.
authors.affiliation: Division de Neuropsychiatrie, Unité de Biochimie Génétique, Hôpitaux Universitaires de Genève, Hôital Belle-Idée, Chêne-Bourg, Switzerland. b-moulard@chu-montpellier.fr
authors.forename: Bruno
authors.initials: B
authors.lastname: Moulard
authors.forename: Pierre
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authors.lastname: Genton
authors.forename: Djamel
authors.initials: D
authors.lastname: Grid
authors.forename: Marc
authors.initials: M
authors.lastname: Jeanpierre
authors.forename: Réda
authors.initials: R
authors.lastname: Ouazzani
authors.forename: Amel
authors.initials: A
authors.lastname: Mrabet
authors.forename: Mike
authors.initials: M
authors.lastname: Morris
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Charlotte
authors.initials: C
authors.lastname: Dravet
authors.forename: François
authors.initials: F
authors.lastname: Mauguière
authors.forename: Barbara
authors.initials: B
authors.lastname: Utermann
authors.forename: Michel
authors.initials: M
authors.lastname: Baldy-Moulinier
authors.forename: Halima
authors.initials: H
authors.lastname: Belaidi
authors.forename: Françoise
authors.initials: F
authors.lastname: Bertran
authors.forename: Arnaud
authors.initials: A
authors.lastname: Biraben
authors.forename: André
authors.initials: A
authors.lastname: Ali Chérif
authors.forename: Taieb
authors.initials: T
authors.lastname: Chkili
authors.forename: Arielle
authors.initials: A
authors.lastname: Crespel
authors.forename: Françoise
authors.initials: F
authors.lastname: Darcel
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Christian
authors.initials: C
authors.lastname: Geny
authors.forename: Véronique
authors.initials: V
authors.lastname: Humbert-Claude
authors.forename: Philippe
authors.initials: P
authors.lastname: Kassiotis
authors.forename: Catherine
authors.initials: C
authors.lastname: Buresi
authors.forename: Alain
authors.initials: A
authors.lastname: Malafosse
mesh_terms: D020413:3' Untranslated Regions; D000352:Africa, Northern; D001483:Base Sequence; D003241:Consanguinity; D055313:Cystatin B; D015891:Cystatins / Q000235:genetics; D004247:DNA / Q000235:genetics; D005060:Europe; D005260:Female; D018703:Founder Effect; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018598:Minisatellite Repeats; D009154:Mutation; D016133:Polymerase Chain Reaction; D013997:Time Factors; D020194:Unverricht-Lundborg Syndrome / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C524994:CSTB protein, human; D015891:Cystatins; D005819:Genetic Markers; D055313:Cystatin B; D004247:DNA