Giant SCA8 alleles in nine children whose mother has two moderately large ones

Corral, Jordi; Genı́s, David; Banchs, Isabel; Nicolás, Hector San; Armstrong, Judith; Volpini, Vı́ctor

doi:10.1002/ana.20421

Cited by 14 publications

(13 citation statements)

References 17 publications

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“…For instance, an expanded CTG tract could have a direct negative impact on KLHL1 expression through interference with essential KLHL1 promoter elements. This direct mechanism, however, would not easily explain the incomplete penetrance of the SCA8 mutation or the observation that extremely large SCA8 repeat expansions do not appear to cause disease (Juvonen et al, 2000(Juvonen et al, , 2005Vincent et al, 2000;Sobrido et al, 2001;Corral et al, 2005). For this reason, we currently believe that mechanisms that require that the expansion be encoded in a transcript are more likely to be correct, because this provides a plausible explanation for the reduced penetrance associated with the SCA8 expansions (e.g., very large repeats may not be transcribed or spliced efficiently and would therefore not generate pathogenic RNA molecules).…”

Section: Discussionmentioning

confidence: 99%

Targeted Deletion of a SingleSca8Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

He¹,

Benzow

et al. 2006

J. Neurosci.

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Spinocerebellar ataxia type 8 (SCA8) patients typically have a slowly progressive, adult-onset ataxia. SCA8 is dominantly inherited and is caused by large CTG repeat expansions in the untranslated antisense RNA of the Kelch-like 1 gene (KLHL1), but the molecular mechanism through which this expansion leads to disease is still unknown. To more fully characterize the underlying molecular mechanisms involved in SCA8, we developed a mouse model in which Klhl1 is deleted in either all tissues or is deleted specifically in Purkinje cells only. We found that mice that are either homozygous or heterozygous for the Klhl1 deletion have significant gait abnormalities at an early age and develop a significant loss of motor coordination by 24 weeks of age. This loss progresses more rapidly in homozygous knock-outs. Mice with Klhl1 specifically deleted in only Purkinje cells had a loss of motor coordination that was almost identical to the total-tissue deletion mice. Finally, we found significant Purkinje cell dendritic deficits, as measured by the thickness of the molecular layer, in all mice in which Klhl1 was deleted (both total and Purkinje cell-specific deletions) and an intermediate reduction in molecular layer thickness in mice with reduced levels of Klhl1 expression (heterozygous deletions). The results from this mouse model show that even a partial loss of Klhl1 function leads to degeneration of Purkinje cell function and indicates that loss of KLHL1 activity is likely to play a significant part in the underlying pathophysiology of SCA8.

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Section: Discussionmentioning

confidence: 99%

Targeted Deletion of a SingleSca8Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

He¹,

Benzow

et al. 2006

J. Neurosci.

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“…The SCA8 mice have revealed a loss of cerebellar GABAergic inhibition and, similar to human patients, intranuclear inclusions containing expanded polyQ in Purkinje cells and other neurons. This recent data could provide a convincing explanation for the lack of penetrance observed in SCA8 patients [68,69].…”

Section: Alterations In Synaptic Neurotransmissionmentioning

confidence: 94%

Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

et al. 2009

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The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. To date, more than 30 genes have been identified triggering the well-described clinical and pathological phenotype, but the underlying cellular and molecular events are still poorly understood. Studies of the functions of the proteins implicated in SCAs and the corresponding altered cellular pathways point to major aetiological roles for defects in transcriptional regulation, protein aggregation and clearance, alterations of calcium homeostasis, and activation of pro-apoptotic routes among others, all leading to synaptic neurotransmission deficits, spinocerebellar dysfunction, and, ultimately, neuronal demise. However, more mechanistic and detailed insights are emerging on these molecular routes. The growing understanding of how dysregulation of these pathways trigger the onset of symptoms and mediate disease progression is leading to the identification of conserved molecular targets influencing the critical pathways in pathogenesis that will serve as effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed cellular and molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the ongoing therapeutic strategies.

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“…In addition coexistence with SCA1, SCA6, 16q-ADCA, FRDA have been reported. In these rare cases the coexisting genetic abnormalities were related to more severe and early onset of symptoms [3][4][5][6].…”

Section: Discussionmentioning

confidence: 93%

“…The reported repeat lengths associated with ataxia usually range from 85 to 130 [2]. In neurodegenerative disorders such as sporadic Parkinson disease (PD) [2] and in ataxias like SCA1, SCA6, 16q-ADCA, and Friedreich's ataxia (FRDA) a rare coexistence of the repeat expansion in the ATXN8 gene has been observed [3][4][5][6]. On the basis of clinical data and neuropathological findings a common pathogenesis has been suggested for SCA6, SCA8 and 16q-ADCA [4].…”

Section: Introductionmentioning

confidence: 94%

Coexisting huntingtin and SCA8 repeat expansion: Case report of a severe complex neurodegenerative syndrome

Bereznai

Lovas

Pentelényi

et al. 2010

Journal of the Neurological Sciences

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Giant SCA8 alleles in nine children whose mother has two moderately large ones

Cited by 14 publications

References 17 publications

Targeted Deletion of a SingleSca8Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

Targeted Deletion of a SingleSca8Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

Coexisting huntingtin and SCA8 repeat expansion: Case report of a severe complex neurodegenerative syndrome

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