Striking Founder Effect for the Fragile X Syndrome in Finland

Oudet, C.; Koskull, Harriet von; Nordström, Ann-Marie; Peippo, Maarit; Mandel, Jean‐Louis

doi:10.1159/000472412

Cited by 52 publications

(30 citation statements)

References 30 publications

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“…In the majority of these, decreased genetic fitness of patients and anticipation associated with a propensity for increased repeat length in succeeding generations leads to loss of expanded alleles over generations. It was therefore unexpected to find strong linkage disequilibrium between disease alleles and close flanking markers, which are an indication of a founder effect (10,(20)(21)(22)(23)(24)(25)(26). This led to the conclusion that the negative selection may be compensated by a (continual) renewal of the larger expansions from a pool of smaller, nonpathologic alleles near the upper limit of the normal size range (10,11,27).…”

Section: Discussionmentioning

confidence: 99%

Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: Founder effect and premutations

Cossée

Schmitt

Campuzano

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

303

242

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Friedreich's ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for Ϸ17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through ''premutation'' intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.

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Section: Discussionmentioning

confidence: 99%

Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: Founder effect and premutations

Cossée

Schmitt

Campuzano

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

303

242

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“…DXS548 (Riggins et al, 1992) and FRAXAC1 , two dinucleotide (CA) repeat markers 150 and 7 kb, respectively, proximal to the CGG repeat, have been the most characterized marker loci used in association studies. Haplotype construction with these markers has revealed linkage disequilibrium between the normal, stable alleles as well as the unstable CGG repeat alleles among individuals with fragile X syndrome in studies of European populations from France and Spain (Oudet et al, 1993a), Belgium and the Netherlands (Buyle et al, 1993), Northern Europe (Riggins et al, 1992), Italy (Chiurazzi et al, 1996a), United Kingdom (Macpherson et al, 1994), Sweden (Malmgren et al, 1994), Finland (Oudet et al, 1993b;Haataja et al, 1994;Zhong et al, 1996), Greece and Cyprus (Patsalis et al, 1999) and Denmark (Larsen et al, 1999(Larsen et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

The FMR1 CGG repeat and linked microsatellite markers in two Basque valleys

et al. 2003

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Fragile X syndrome is associated with an unstable CGG repeat sequence in the 5 0 untranslated region of the first exon of the FMR1 gene. The present study involved the evaluation of factors implicated in CGG repeat stability in a normal sample from two Basque valleys (Markina and Arratia), to discover whether the Basque population shows allelic diversity and to identify factors involved, by using the data in conjunction with previous findings. The study was based on a sample of 204 and 58 X chromosomes from the Markina and Arratia valleys, respectively. The CGG repeat, the AGG interspersion and two flanking microsatellite markers, FRAX-AC1 and DXS548, were examined. In the Markina valley, gray zone alleles (X35 CGG repeats) were associated with anchoring AGGs, with the longest 3 0 pure CGG repeats of the valley ( ¼ 15), with the 5 0 instability structure 9+n and with one principal fragile X FRAXAC1-DXS548 haplotype 42-50. In the Arratia valley, gray zone alleles (X35 CGG repeats) showed the highest frequency among the Basque samples analyzed, and were associated with anchoring AGGs, with the longest 3 0 pure repeats (X20), with the 5 0 instability structure 9+n and with one 'normal' FRAXAC1-DXS548 haplotype 38-40 (these data from Arratia suggest the existence of a 'protective' haplotype). The results showed, on the one hand, differences between Markina and Arratia in factors implicated in CGG repeat instability and, on the other hand, a great similarity between the general Basque sample from Biscay and the Markina valley.

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“…. was also found that allele distributio ns are different on fragile X chromo somes compared with normal X chromo somes, giving furth er support to the suggestion of a fragile X founder effect (73)(74)(75)(76)(77). The data argue for a limited numb er of independent mutations that provided the origin of most of the present-day fragil e X chromosomes and may expl ain the unexpected long history of some of these fragile X mutations (78,79).…”

Section: Mechanism and Timing Of Repeat Amplificationmentioning

confidence: 67%