Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations

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...

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Bibliographic Details
Published in:	Human genetics Vol. 111; no. 3; pp. 255 - 262
Main Authors:	MOULARD, Bruno, GENTON, Pierre, UTERMANN, Barbara, BALDY-MOULINIER, Michel, BELAIDI, Halima, BERTRAN, Francoise, BIRABEN, Arnaud, CHERIF, André Ali, CHKILI, Taieb, CRESPEL, Arielle, DARCEL, Francoise, DULAC, Olivier, GRID, Djamel, GENY, Christian, HUMBERT-CLAUDE, Véronique, KASSIOTIS, Philippe, BURESI, Catherine, MALAFOSSE, Alain, JEANPIERRE, Marc, OUAZZANI, Réda, MRABET, Amel, MORRIS, Mike, LEGUEM, Eric, DRAVET, Charlotte, MAUGUIERE, Francois
Format:	Journal Article
Language:	English
Published:	Heidelberg Springer 01-09-2002 Berlin Springer Nature B.V New York, NY
Subjects:	3' Untranslated Regions Africa, Northern Base Sequence Biological and medical sciences Consanguinity Cystatin B Cystatins - genetics Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases DNA - genetics Europe Female Founder Effect Fundamental and applied biological sciences. Psychology Genetic Markers Genetics of eukaryotes. Biological and molecular evolution Haplotypes Human Humans Linkage Disequilibrium Male Medical sciences Minisatellite Repeats Mutation Neurology Polymerase Chain Reaction Population genetics, reproduction patterns Time Factors Unverricht-Lundborg Syndrome - genetics Africa, Northern Europe Human Nervous system diseases Genetic marker Transcription promoter Repeated sequence Chromosome Progressive myoclonus epilepsy Founder effect Cerebral disorder Variant Central nervous system disease Genetics Population Degenerative disease Mutation Expansion Haplotype
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Summary:	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.
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ISSN:	0340-6717 1432-1203
DOI:	10.1007/s00439-002-0755-x