Friedreich ataxia in carriers of unstable borderline GAA triplet‐repeat alleles

Sharma, Rajesh; Biase, Irene De; Gómez, María Mercedes; Delatycki, Martin B.; Ashizawa, Tetsuo; Bidichandani, Sanjay I.

doi:10.1002/ana.20333

Cited by 47 publications

(43 citation statements)

References 11 publications

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“…This disease is caused by the loss of transcription of the frataxin gene as a result of the genetic expansion of 30 2* − 0.0502 −22 (GAA•TTC) 60 1 − 0.0537 −24 (GAA•TTC) 60 2* + 0.0305 −14 (GAA•TTC) 176 1 − 0.0505 −24 (GAA•TTC) 176 2* + 0.0266 −14 (GAA•TTC) 176 2** − 0.0501 −27 (CG•CG) 22 1 − 0.0581 −24…”

Section: Discussionmentioning

confidence: 98%

“…The plasmids analyzed were pRW1628 (vector) (black), pRW4886 (royal blue), pRW4882 (green), pRW4887 (light blue), pRW4876 (red), pRW4892 (yellow), pRW4893 (pink) and pRW4894 (purple). Inset: analysis of pRW1564 which is a pBR322 derivative, containing one tract of (CG•CG) 22 and has the ability to form Z-DNA. 47 The data for this plasmid were compared to the average negative supercoil density of the vector.…”

Section: Discussionmentioning

confidence: 99%

“…To verify that other non-B DNA structures, known to cause and increase in −σ in vivo, behaved in the same manner under our experimental conditions, we tested a plasmid that contained one tract of (CG•CG) 22 , which forms left-handed Z-DNA. As predicted, the B to Z transition of the 44 bp led to an increase in the average negative supercoiling in vivo (−0.0581), which is similar to previous calculations of Z-DNA forming plasmids (Figure 7, inset).…”

Section: Sticky Dna Decreases the Apparent Negative Supercoiling In Vivomentioning

confidence: 90%

“…13,[15][16][17][18][19] The expansion of the GAA•TTC sequence is effected by replication, recombination and repair. 14,[20][21][22][23][24][25] Once expanded, the repeat may influence the function of these mechanisms. Long GAA•TTC repeats were shown to stall replication forks in vivo in Saccharymyces cerevisiae.…”

Section: Introductionmentioning

confidence: 98%

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Sticky DNA: in Vivo Formation in E. coli and in Vitro Association of Long GAA•TTC Tracts to Generate Two Independent Supercoiled Domains

Son

Bacolla

Wells

2006

Journal of Molecular Biology

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Sticky Dna Decreases the Apparent Negative Supercoiling In Vivomentioning

confidence: 90%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Sticky DNA: in Vivo Formation in E. coli and in Vitro Association of Long GAA•TTC Tracts to Generate Two Independent Supercoiled Domains

Son

Bacolla

Wells

2006

Journal of Molecular Biology

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“…The number of GAA repeats correlates with the reduction in frataxin expression, which correlates, in turn, with disease severity. Larger GAA expansion results in an earlier age of onset; loss of ambulation occurs earlier [89][90][91][92]. Another source of variability in the clinical presentation of FA are mutations within the FRX gene [93], present in 1-5% of the affected individuals.…”

Section: Friedreich's Ataxiamentioning

confidence: 97%

Genetic and phenotypic variability of optic neuropathies

Neuhann

Rautenstrauß

2013

Expert Review of Neurotherapeutics

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Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Two subgroups can be formed: isolated hereditary optic atrophies and optic neuropathy as part of complex disorders. In group 1 of hereditary optic neuropathies, optic nerve dysfunction is typically the only manifestation of the disease. This group comprises autosomal dominant, autosomal recessive and X-linked recessive optic atrophy and the maternally inherited Leber's hereditary optic neuropathy. Among the autosomal-dominant forms of optic atrophy, Kjer's disease is most frequently observed. In the second group of complex disorders, various neurologic and other systemic abnormalities are regularly observed. Most frequent in this group are mtDNA mutations, inherited peripheral neuropathies, Charcot-Marie-Tooth disorders (CMT2A2, CMTX5), hereditary sensory neuropathy type 3 (HSAN3), Friedreich's ataxia, leukodystrophies, sphingolipidoses, ceroid-lipofuscinoses and neurodegeneration with brain iron accumulation. We review current knowledge about the underlying genetic predispositions, the most urgent open questions and how this may affect our management of this heterogeneous group of disorders in the future.

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Progressive gaa expansions in dorsal root ganglia of Friedreich's ataxia patients

Biase

Rasmussen

Endres

et al. 2007

Annals of Neurology

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107

111

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Objective: Friedreich's ataxia patients are homozygous for expanded alleles of a GAA triplet-repeat sequence in the FXN gene. Patients develop progressive ataxia due to primary neurodegeneration involving the dorsal root ganglia (DRGs). The selective neurodegeneration is due to the sensitivity of DRGs to frataxin deficiency; however, the progressive nature of the disease remains unexplained. Our objective was to test whether the expanded GAA triplet-repeat sequence undergoes further expansion in DRGs as a possible mechanism underlying the progressive pathology seen in patients. Methods: Small-pool polymerase chain reaction analysis, a sensitive technique that allows the measurement of repeat length in individual FXN genes, was used to analyze somatic instability of the expanded GAA triplet-repeat sequence in multiple tissues obtained from six autopsies of Friedreich's ataxia patients. Results: DRGs showed a significantly greater frequency of large expansions ( p Ͻ 0.001) and a relative paucity of large contractions compared with all other tissues. There was a significant age-dependent increase in the frequency of large expansions in DRGs, which ranged from 0.5% at 17 years to 13.9% at 47 years (r ϭ 0.78; p ϭ 0.028). Interpretation: Progressive pathology involving the DRGs is likely due to age-dependent accumulation of large expansions of the GAA triplet-repeat sequence. Thus, somatic instability of the expanded GAA triplet-repeat sequence may contribute directly to disease pathogenesis and progression. Progressive repeat expansion in specific tissues is a common theme in the pathogenesis of triplet-repeat diseases.Ann Neurol 2007;61: [55][56][57][58][59][60] Friedreich's ataxia (FRDA) is characterized by progressive sensory ataxia with onset before 25 years of age, areflexia, loss of position and vibration senses, dysarthria, and extensor plantar responses. 1 Patients have primary degeneration of dorsal root ganglia (DRGs), associated with axonal degeneration of the posterior columns, spinocerebellar tracts, and corticospinal tracts, and large myelinated fibers in peripheral nerves. 2 In later stages, the cerebellum may be affected; however, other regions of the nervous system remain unaffected. Two-thirds of patients have cardiomyopathy. Although the rate of progression is variable, the mean age of loss of ambulation is 25 years, and patients often die prematurely. 1 FRDA is an autosomal recessive disease, and most patients are homozygous for expanded GAA tripletrepeat sequences (E alleles) in intron 1 of the FXN gene. 3 E alleles interfere with transcription in a lengthdependent manner, 4 resulting in deficiency of the mitochondrial protein frataxin. 5 E alleles contain 66 to 1,700 triplets, and the severity of disease and rate of progression correlate with repeat length. 6 -8 DRG neurons are hypersensitive to frataxin deficiency as seen in neuronal-specific, conditional, frataxin knock-out mice. 9 However, this mouse model did not accurately mimic the situation in FRDA, because the mice had normal levels th...

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Friedreich ataxia in carriers of unstable borderline GAA triplet‐repeat alleles

Cited by 47 publications

References 11 publications

Sticky DNA: in Vivo Formation in E. coli and in Vitro Association of Long GAA•TTC Tracts to Generate Two Independent Supercoiled Domains

Sticky DNA: in Vivo Formation in E. coli and in Vitro Association of Long GAA•TTC Tracts to Generate Two Independent Supercoiled Domains

Genetic and phenotypic variability of optic neuropathies

Progressive gaa expansions in dorsal root ganglia of Friedreich's ataxia patients

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