Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia.

Fujita, Ricardo; Hanauer, André; Sirugo, Giorgio; Heilig, Roland; Mandel, Jean‐Louis

doi:10.1073/pnas.87.5.1796

Cited by 41 publications

(31 citation statements)

References 15 publications

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“…Although the number of haplotypes tested is still relatively small, this suggests that unstable alleles derive from LN alleles by recurrent events rather than by a very small number of secondary founder events. On the other hand, the previous finding of significant linkage disequilibrium with markers located 700 to 500 kb from the GAA in French, Italian, Tunisian, Reunion island, and Cajun patients (12,14,36) suggests that such secondary events generating unstable alleles (premutated) are not very frequent. By comparison with estimates made on the age of BRCA1 mutations showing linkage disequilibrium over comparable distances (37), we suggest that the secondary events accounting for the most frequent extended haplotypes seen in FRDA patients of such populations could be at least 30 generations old.…”

Section: Discussionmentioning

confidence: 78%

“…The GAA repeat is moderately polymorphic among normal alleles. The distribution is bimodal; most (83%) alleles contain around nine repeats (7)(8)(9)(10)(11)(12), and 17% are LN alleles of 16 repeats or more. Accurate sizing was determined on 26 SN and 65 LN GAA alleles by denaturing polyacrylamide gel migration.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, because this is a recessive disease, there is no strong selection pressure on pathological alleles (unlike in myotonic dystrophy or fragile X syndrome). Significant linkage disequilibrium was initially detected in French and Italian FRDA patients using markers now known to lie at 700 and 500 kb from the frataxin gene (12)(13)(14). A stronger disequilibrium, suggestive of a major founder effect, was detected further by analysis of a biallelic marker located 120 kb telomeric to the frataxin GAA repeat (15).…”

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confidence: 99%

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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: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…The primary defect underlying the selective cellular degeneration in FRDA remains unknown but the inherited nature of the disease (autosomal recessive) should allow identification ofthe defective gene by positional cloning. The FRDA gene was localized on chromosome 9 in 1988 (2) and extensive genetic and physical mapping of the locus has been done since then (3)(4)(5)(6)(7)(8)(9)(10). These studies showed that the FRDA locus is most tightly linked to the two independently isolated loci D9S5 and D9S15 that lie only 250 kilobases (kb) apart.…”

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confidence: 99%

Gene in the region of the Friedreich ataxia locus encodes a putative transmembrane protein expressed in the nervous system.

Duclos

Boschert

Sirugo

et al. 1993

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

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Friedreich ataxia (FRDA) is an autosomal recessive degenerative disorder that affects the cerebellum, spinal cord, and peripheral nerves. The FRDA gene was localized in 9q13-q21 within 0.7 centimorgan of the D9SS and D9S15 loci. One recently reported recombination event and haplotype analysis in a population with a founder effect suggested that the FRDA locus is on the D9S5 side. Using a conserved probe from the D9SS locus, we have now identified an -7-kilobase (kb) transcript and report cloning of its cDNA. The corresponding gene, XlI, extends at least 80 kb in a direction opposite D9S15. The gene is expressed in the brain, including the cerebellum, but is not detectable in several nonneuronal tissues and cell lines. In situ hybridization of adult mouse brain sections showed prominant expression in the granular layer of the cerebellum. Expression was also found in the spinal cord. The cDNA contains an open reading frame encoding a 708-amino acid sequence that shows no significant similarity to other known proteins but contains a unique, 24-residue-long, putative transmembrane segment. On the basis of its genomic localization and its neuronal site of expression, particularly in the cerebellum, this "pioneer'" gene represents a candidate for FRDA. Direct evidence of its involvement in FRDA will require a search for causative point mutations in patients.Friedreich ataxia (FRDA) is a degenerative disorder involving both the central and peripheral nervous systems (1). It is characterized by progressive gait and limb ataxia, loss of position and vibration sense, loss of tendon reflexes in the lower limbs, and dysarthria. Neurological symptoms correlate with degeneration in the dorsal root ganglia, the posterior columns and spinocerebellar tracts ofthe spinal cord, and the cerebellum. In peripheral nerves, severe loss of thick myelinated fibers is found. Other symptoms are frequently found and usually occur as the disease progresses: pyramidal weakness of the legs, Babinski sign, scoliosis, cardiomyopathy, and pes cavus. An increased risk of diabetes mellitus seems to be associated with the disease. The primary defect underlying the selective cellular degeneration in FRDA remains unknown but the inherited nature of the disease (autosomal recessive) should allow identification ofthe defective gene by positional cloning. The FRDA gene was localized on chromosome 9 in 1988 (2) and extensive genetic and physical mapping of the locus has been done since then (3-10). These studies showed that the FRDA locus is most tightly linked to the two independently isolated loci D9S5 and D9S15 that lie only 250 kilobases (kb) apart. Very recently, however, rare recombination events were reported that appeared to exclude the gene from the region between D9S15 and the 26P marker at D9S5 (12, 13). One of these recombinants (13), as well as the analysis of FRDA-linked haplotypes in a population with a founder effect (14), suggested that the disease gene lies on the D9S5 side of the D9SJ5-D9S5 interval. Evolutionarily conserved seq...

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“…Only for D9S15 [21,22,27,28] and D9S11 [28] are allele frequencies from other populations known. In all studies at D9S15, allele 3 is more frequent in FRDA chromosomes in contrast to control chromosomes, whereas allele 6 is overrepresented in control chromosomes.…”

Section: Resultsmentioning

confidence: 99%

Linkage Disequilibrium and Haplotype Analysis in German Friedreich Ataxia Families

et al. 1999

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The main mutation causing Friedreich ataxia (FRDA) is the expansion of a GAA repeat localized within the intron between exon 1 and exon 2 of the gene X25. This expansion has been observed in 98% of FRDA chromosomes. To analyze frequencies of markers tightly linked to the Friedreich ataxia gene and to investigate wheter a limited number of ancestral chromosomes are shared by German FRDA families, a detailed analysis employing nine polymorphic markers was performed. We found strong linkage disequilibria and association of FRDA expansions with a few haplotypes. FRDA haplotypes differ significantly from control haplotypes. Our results confirm that GAA repeat expansions in intron 1 of the frataxin gene are limited to a few chromosomes and indicate an obvious founder effect in German patients. Based on these analyses, we estimate a minimum age of the mutation of 107 generations.

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Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia.

Cited by 41 publications

References 15 publications

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

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

Gene in the region of the Friedreich ataxia locus encodes a putative transmembrane protein expressed in the nervous system.

Linkage Disequilibrium and Haplotype Analysis in German Friedreich Ataxia Families

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