An expanded CAG repeat sequence in spinocerebellar ataxia type 7.

Lindblad, Kerstin; Savontaus, Marja Liisa; Stevanin, Giovanni; Holmberg, Monica; Digre, Kathleen B.; Zander, Cecilia; Ehrsson, H. Henrik; David, Gilles; Benomar, Ali; Nikoskelainen, Eeva; Trottier, Yvon; Holmgren, Gösta; Ptáček, Louis J.; Anttinen, Anu; Brice, Alexis; Schalling, Martin

doi:10.1101/gr.6.10.965

Cited by 98 publications

(48 citation statements)

References 20 publications

(22 reference statements)

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“…All reactions were performed and analysed as previously reported using 15 U Ampligase per reaction. 16 CTG18.1 PCR Primers 7.6A-upper (5Ј-AAT CCA AAC CGC CTT CCA AGT-3Ј) and 7.6A-lower (5Ј-CAA AAC TTC CGA AAG CCA TTT CT-3Ј) were used. 20 PCR reactions containing 40-100 ng genomic DNA, 0.5 M of each primer, 5% DMSO, 0.2 mM dNTPs, 50 mM KCl, 1.5 mM MgCl 2 , 10 mM Tris pH = 8.3 and 0.1% gelatine in 20 l, were amplified by 5 min primary denaturation at 95°C followed by 15 cycles of 91°C for 50 s, 56°C for 100 s and 72°C for 60 s and 15 cycles of 94°C for 50 s, 56°C for 100 s, 72°C for 60 s and a final extension of 6 min at 72°C.…”

Section: Dna Preparationmentioning

confidence: 99%

“…Anticipation has been described in both bipolar [7][8][9] and unipolar 10 affective disorder and recently there have been reports of enlarged CAG/CTG repeats in bipolar disorder using the RED method. [11][12][13][14] In RED 15,16 a thermostable ligase is used in a cycling procedure to detect TREs directly from genomic DNA without information of their location in the genome. The reaction products can, after a series of steps, be visualised as a ladder of bands, where the top band corresponds to the longest repeat sequence present in the genome tested.…”

Section: Introductionmentioning

confidence: 99%

“…The RED assay has previously been used for detection of pathogenic TREs in several dis-orders, including myotonic dystrophy, 15 MachadoJoseph disease 17 and spinocerebellar ataxia type 7. 16 Two recently identified loci, ERDA1 (also known as Dir-I) on chromosome 17q21.3 18,19 and CTG18.1 (also known as 7.6A) on chromosome 18q21.1, 20 display expanded alleles in normal individuals. CTG18.1 is a particularly interesting locus as it is present within a gene that is expressed in multiple organs including the brain.…”

Section: Introductionmentioning

confidence: 99%

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Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

et al. 1998

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An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) Ͼ120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P Ͻ 0.07) with a significantly different size distribution (P Ͻ 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products Ͼ120 nt. The RED product distribution was significantly different (P Ͻ 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P Ͻ 0.04) of CTG18.1 expansions as well as a different (P Ͻ 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (r s = −0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.

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Section: Dna Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

et al. 1998

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“…To date, 9 polyQ diseases have been identified: spinal-bulbar muscular atrophy (SBMA) [1], Huntington disease (HD) [2], spinocerebellar ataxia (SCA) type 1 (SCA1) [3], SCA type 3 (SCA3) [4], dentatorubral-pallidoluysian atrophy (DRPLA) [5], SCA type 2 (SCA2) [6], SCA type 7 (SCA7) [7], SCA type 6 (SCA6) [8], and SCA type 17 (SCA17) [9]. All of these diseases share autosomal dominant inheritance, with the exception of SBMA, which shows Xlinked inheritance.…”

Section: Introductionmentioning

confidence: 99%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

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Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.

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“…[1][2][3][4][5][6][7][8][9][10][11] Expansion of polyglutamine repeats is associated with a toxic gain-of-function that affects specific neuronal populations in each of these diseases. 12 Huntington's disease (HD), one of the most extensively studied of these diseases, is a debilitating inherited neurodegenerative disorder characterized by involuntary movements, personality changes, dementia, and early death.…”

Section: Introductionmentioning

confidence: 99%

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

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Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

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An expanded CAG repeat sequence in spinocerebellar ataxia type 7.

Cited by 98 publications

References 20 publications

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

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