Confirmation of linkage of Friedreich ataxia to chromosome 9 and identification of a new closely linked marker

Fujita, Ricardo; Agid, Yves; Trouillas, P; Seck, Abdoulaye; Tommasi-Davenas, Christine; Driesel, A.J.; Olek, K.; Grzeschik, Karl‐Heinz; Nakamura, Yusuke; Mandel, Jean Louis; Hanauer, André

doi:10.1016/0888-7543(89)90323-6

Cited by 64 publications

(24 citation statements)

References 8 publications

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“…Chamberlain et al (4) mapped the FA gene (FRDA in the Human Gene Mapping Workshop nomenclature) to chromosome 9 by virtue of its tight linkage to the polymorphic locus D9S15 (probe pMCT112). We confirmed this linkage in another set of families and identified a second closely linked marker locus, D9S5 (5). So far, D9S15 and D9S5 have displayed no recombination with FRDA or between themselves in all informative meioses examined.…”

supporting

confidence: 65%

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

Fujita

Hanauer

Sirugo

et al. 1990

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

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The gene for Friedreich ataxia (FA), a severe recessive neurodegenerative disease, has previously been shown to be tightly linked to the polymorphic markers D9S15 and D9S5 on human chromosome 9. In addition, the observation of linkage disequilibrium suggested that D9S15 is within 1 centimorgan (cM) of the disease locus, FRDA. Although D9SS did not show recombination with F-RDA, its localization was less precise (0-5 cM) due to its lower informativeness. We have now identified additional polymorphisms at both marker loci. Two cosmids spanning 50 kilobases around D9SS were isolated, and a probe derived from one of them detects an informative three-allele polymorphism. We have found a highly polymorphic microsatellite sequence at D9Sl5 which is rapidly typed by the DNA polymerase chain reaction. The polymorphism information contents at the D9S5 and D9S15 loci have been increased from 0.14 to 0.60 and from 0.33 to 0.74, respectively. between themselves in all informative meioses examined. The combination of our data with those published by Chamberlain et al. (6) showed that D9S15 is within one centimorgan (cM) ofthe disease locus (7). The linkage data, combined with physical mapping of D9S5 by in situ hybridization, support the assignment of FRDA to the proximal long arm of chromosome 9 (7). The very close proximity of D9S15 to FRDA was further indicated by the finding of a significant allelic association between FRDA and the Msp I restriction fragment length polymorphism (RFLP) at D9S15. In contrast, no linkage disequilibrium was noted between FRDA and previously described RFLPs at D9S5 (7). Several families in our initial linkage analysis were partially or completely uninformative, especially for D9SM. In an attempt to refine the genetic map around the FRDA locus and to further explore the linkage disequilibrium, a search has been conducted for new informative polymorphisms at the marker loci. We have isolated two overlapping cosmid clones which extend the D9S5 locus over 50 kilobases (kb). Additional RFLPs have been revealed by single-copy probes derived from these cosmids. One ofthese (probe 26P) detects a three-allele BstXI RFLP that increases considerably the heterozygosity of D9SM. We have also characterized within probe MCT112 (D9S15) a highly polymorphic "microsatellite" sequence (8,9). This allowed us to confirm that D9S5 and D9S15 are very tightly linked to FRDA. By using these polymorphisms at both loci, extended haplotypes can be generated, and some of them show highly significant linkage disequilibrium with FRDA. MATERIALS AND METHODSLinkage Studies. Forty-one FA families (34 from France), each with at least two affected children, were studied. Thirty-eight of these families have been previously analyzed for the Msp I RFLPs at D9S5 and D9S15 (7). All of these families conform to the diagnostic criteria for typical FA (1, 2). Southern blot analysis was performed as described (7). Linkage analysis was carried out by using the LINKAGE program (10) and the lod-1 support interval (lod = logl0 odds r...

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supporting

confidence: 65%

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

Fujita

Hanauer

Sirugo

et al. 1990

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

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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.…”

mentioning

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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“…The gene for this autosomal recessive neurodegenerative disease has been mapped to chromosome 9q13-q21.1 by linkage studies (1,2). The clinical features and molecular biology FRDA have been reviewed (3)(4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Sticky DNA, a Long GAA·GAA·TTC Triplex That Is Formed Intramolecularly, in the Sequence of Intron 1 of the Frataxin Gene

Vetcher

Напиерала

Iyer

et al. 2002

Journal of Biological Chemistry

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Friedreich's ataxia is caused by the massive expansion of GAA⅐TTC repeats in intron 1 of the frataxin (X25) gene. Our prior investigations showed that long GAA⅐TTC repeats formed very stable triplex structures which caused two repeat tracts to adhere to each other (sticky DNA). This process was dependent on negative supercoiling and the presence of divalent metal ions. Herein, we have investigated the formation of sticky DNA from plasmid monomers and dimers; sticky DNA is formed only when two tracts of sufficiently long (GAA⅐TTC) n (n ‫؍‬ 59 -270) are present in a single plasmid DNA and are in the direct repeat orientation. If the inserts are in the indirect (inverted) repeat orientation, no sticky DNA was observed. Furthermore, kinetic studies support the intramolecular nature of sticky DNA formation. Electron microscopy investigations also provide strong data for sticky DNA as a single long triplex. Hence, these results give new insights into our understanding of the capacity of sticky DNA to inhibit transcription and thereby reduce the level of frataxin protein as related to the etiology of Friedreich's ataxia.Friedreich's ataxia (FRDA) 1 is the most common hereditary ataxia. The gene for this autosomal recessive neurodegenerative disease has been mapped to chromosome 9q13-q21.1 by linkage studies (1, 2). The clinical features and molecular biology FRDA have been reviewed (3-10). The FRDA gene, X25, contains seven exons and encodes a 210-amino acid protein called frataxin (8). The vast majority of FRDA patients have an expanded GAA⅐TTC repeat in the first intron of the frataxin gene. Normal alleles have 6 -34 repeats of GAA⅐TTC repeats, but FRDA-associated alleles have 66 -1,700 or more GAA⅐TTC repeats (3,8,10). FRDA is the only triplet repeat disease that has a recessive inheritance pattern and is caused by the expansion of a GAA⅐TTC repeat (9).The age of onset and the severity of the disease are correlated with the length of the GAA⅐TTC repeats (8,11,12). Patients carrying expanded GAA⅐TTC repeats in both alleles have reduced levels of frataxin, and an inverse correlation exists between the size of the GAA⅐TTC repeat and amount of the frataxin protein (13,14). This reduction in the amount of the frataxin protein is caused by a diminution in the amount of the frataxin mRNA (8,15,16). The amount of the X25 mRNA is inversely related to the length of the GAA⅐TTC repeat both in vitro (17) and in vivo (18). Virtually all workers in the field have proposed that the long GAA⅐TTC repeats form triplexes (three stranded DNA structures) that are involved in the transcriptional inhibition (16 -22). In fact, recent investigations (22) directly demonstrated that sticky DNA (a complex triplex formed at GAA⅐TTC repeats; described below) inhibits transcription in vitro, and in vivo investigations (18, 23) are consistent with these results.Substantial prior investigations (19, 24 -29) showed that shorter GAA⅐TTC inserts (16 -58 repeats) adopt triplex structures. DNA triplexes are formed at polypurine⅐polypyrimidine (R⅐Y) t...

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Confirmation of linkage of Friedreich ataxia to chromosome 9 and identification of a new closely linked marker

Cited by 64 publications

References 8 publications

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

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

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

Sticky DNA, a Long GAA·GAA·TTC Triplex That Is Formed Intramolecularly, in the Sequence of Intron 1 of the Frataxin Gene

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