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.

Founder Effect and Estimation of the Age of the c.892C>T (p.Arg298Cys) Mutation in LMNA Associated to Charcot‐Marie‐Tooth Subtype CMT2B1 in Families from North Western Africa

“…The relative homogeneity of populations from the Maghreb has often been underlined, and several founder mutations/effects have already been reported in North African (including Algerian) populations for various autosomal recessive hereditary diseases, such as: limb girdle muscular dystrophy type LGMD2C (Noguchi et al 1995), ataxia with isolated vitamin E deficiency (AVED) (Ouahchi et al 1995), Allgrove syndrome (Genin et al 2004), Unverricht-Lundborg disease (ULD) (Moulard et al 2002), Parkinson disease (Lesage et al 2005), Mal de Meleda disease (MdM) (Fischer et al 1998), Familial Mediterranean Fever (Belmahi et al 2006), or ß-thalassemias (Bennani et al 1994).…”

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

“…Other cis-acting elements include the composition and number of repeats. EPM1 is similar to many other repeat expansion disorders in that the mutant alleles have common haplotypes in several different populations, presumably due to a founder effect (Lehesjoki et al, 1993b(Lehesjoki et al, , 1994Richards, 2001;Moulard et al, 2002). Recently it was shown in mice that changing the flanking genomic sequences of the SCA7 CAG repeat dramatically altered repeat stability (Libby et al, 2003).…”

A Shared Haplotype Indicates a Founder Event in Unverricht–Lundborg Disease Patients from Serbia

“…Haplotype analysis of chromosomes with the expansion in the CSTB from Northern African and Western European patients showed connection between the expansion and two main haplotypes, A and C, implying that there were only a few founder mutations associated with ULD worldwide [4].…”

“…We performed haplotype analysis using eight genetic markers in order to examine if the most common ULD mutation is founder mutation in Serbia or is it one of a few founder mutations worldwide [4], and estimated the period of its introducing to Serbia.…”

“…The disease has variable rate of progression within and between families [1]. ULD is the most prevalent around the Baltic Sea and in the western Mediterranean region [2][3][4], but many sporadic cases are reported worldwide [5][6][7][8][9][10].…”