Mapping of mutation causing Friedreich's ataxia to human chromosome 9

Chamberlain, Susan; Shaw, Jacqui; Rowland, Alison; Wallis, Julie; South, S.; Nakamura, Yusuke; Gabain, Alexander von; Farrall, Martin; Williamson, Robert

doi:10.1038/334248a0

Cited by 278 publications

(102 citation statements)

References 21 publications

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“…Therefore, efforts to understand the disorder are directed towards isolating the disease gene on the basis of its genomic map position. 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).…”

mentioning

confidence: 99%

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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mentioning

confidence: 99%

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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“…Clinical diagnostic criteria for typical cases basically include: a) early age of onset < 20 16 or 25 years 17 , b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. Chamberlain et al (1988) 8 mapped the Friedreich's ataxia gene to chromosome 9, which was subsequently confirmed 15 . Later, recombinant events 3 allowed the successive narrowing of the candidate region 7,10,22,26 .…”

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confidence: 76%

Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

Albano¹,

Zatz²,

Kim³

et al. 2001

Rev. Hosp. Clin.

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Introduction: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes.Methods: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia -19 typical and 6 atypical -using a long-range PCR test.Results: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) -all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions.Discussion: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion. DESCRIPTORS: Friedreich's ataxia. Trinucleotide expansion repeats. GAA expansion.Friedreich's ataxia (FA) (OMIM 277460) 23 , a neurodegenerative disorder, is the most frequent form of hereditary ataxia, with a prevalence of 1:50,000. Clinical diagnostic criteria for typical cases basically include: a) early age of onset < 20 16 or 25 years 17 , b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. Chamberlain et al. (1988) 8 mapped the Friedreich's ataxia gene to chromosome 9, which was subsequently confirmed 15 . Later, recombinant events 3 allowed the successive narrowing of the candidate region 7,10,22,26 . Campuzano et al. (1996) 6 detected in about 96% of Friedreich's ataxia patients an expanded GAA (guanine, adenine, and adenine) trinucleotide repeat in intron 1 of the gene X25 (with 7 exons-1 to 5a, 5b, and 6-spanning 95 kb of genomic DNA) that encodes a 210-amino acid protein, frataxin, whose function is unknown. Absence of deep tendon reflexes in lower limbs has been included in the diagnostic criteria both by the Geoffroy et al. (1976) and Harding (1981) 16,17 ; however, clinical variability has been reported 11,14 , especially related to the 144 REV. HOSP. CLÍN. FAC. MED. S. PAULO 56(5): [143][144][145][146][147][148] 2001 SEPTEMBER-OCT...

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“…1,10,11) The hypothesis that FRDA is due to accumulation of mitochondrial iron leading to increased production of free radicals impairing the mitochondria and cell functions was more directly evidenced by Delatycki, et al 10,[12][13][14][15] Studies have reported a relationship between the number of GAA repeats in the smaller frataxin allele and cardiomyopathy in about two-thirds of patients homozygous for the GAA expansion. [16][17][18] Isnard, et al showed that the severity of left ventricular hypertrophy was related to the number of GAA repeats.…”

Section: Discussionmentioning

confidence: 99%

The Evaluation of Left Ventricular Systolic and Diastolic Functions in Patients With Friedreich Ataxia A Pulse Tissue Doppler Study

et al. 2005

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SUMMARYFriedreich's ataxia (FRDA), the most common subtype of early onset hereditary ataxia, is an autosomal recessive neurodegenerative disorder caused by unstable GAA expansions. Two-dimensional, pulse, and pulse tissue Doppler echocardiographic examinations were performed on 21 patients with GAA expansion.There was no association between left ventricle ejection fraction, tissue Doppler systolic s wave, and left ventricle diastolic functions examined by pulse and tissue Doppler. The septum thickness of patients with Friedreich's ataxia was significantly increased when compared with that of the control group and wall thickness was found to be associated with GAA repeats.In patients with FRDA, despite a correlation between genetic abnormality with left ventricular early and late diastolic parameters, global diastolic functions were preserved when examined by tissue Doppler. (Int Heart J 2005; 46: 443-452)

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Mapping of mutation causing Friedreich's ataxia to human chromosome 9

Cited by 278 publications

References 21 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.

Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

The Evaluation of Left Ventricular Systolic and Diastolic Functions in Patients With Friedreich Ataxia A Pulse Tissue Doppler Study

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