On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family

Martin, Jean‐Jacques; Regemorter, N. Van; Krols, Luc; Brucher, J. M.; Barsy, Thierry de; Szliwowski, Henri; Evrard, Philippe; Ceuterick, C.; Tassignon, Marie-José; Smet-Dieleman, H.; Hayez-Delatte, F.; Willems, Patrick J.; Broeckhoven, Christine Van

doi:10.1007/bf00310370

Cited by 93 publications

(48 citation statements)

References 22 publications

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“…Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder characterized by cerebellar and retinal degeneration (Martin et al, 1994). SCA7 is caused by a CAG / polyglutamine (polyQ) repeat expansion in the ataxin-7 gene, and is therefore one of nine polyQ neurodegenerative disorders (La Spada and Taylor, 2010).…”

Section: Introductionmentioning

confidence: 99%

CTCF Regulates Ataxin-7 Expression through Promotion of a Convergently Transcribed, Antisense Noncoding RNA

Sopher

Ladd

Pineda

et al. 2011

Neuron

122

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Summary Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG / polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription co-activator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated. The ataxin-7 repeat and translation start site are flanked by binding sites for CTCF, a highly conserved multi-functional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense non-coding RNA, SCAANT1. To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is required for SCAANT1 expression. Loss of SCAANT1 de-repressed ataxin-7 sense transcription in a cis-dependent fashion, and was accompanied by chromatin remodeling. Discovery of this pathway underscores the importance of altered epigenetic regulation for disease pathology at repeat loci exhibiting bidirectional transcription.

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Section: Introductionmentioning

confidence: 99%

CTCF Regulates Ataxin-7 Expression through Promotion of a Convergently Transcribed, Antisense Noncoding RNA

Sopher

Ladd

Pineda

et al. 2011

Neuron

122

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“…Vulnerable neurons in SCA7 include Purkinje cells, a neuronal population that is affected in most polyQ-mediated SCAs, excepted SCA3 [14], and several other neuronal populations such as cerebellar granule cells, neurons of inferior olive and cranial nerve nuclei, and also rod-cone photoreceptors, a cell population that is spared in other SCA types [15]–[17]. Beside this disease-specific neuronal vulnerability, all polyQ disorders share several common features: ( i ) progressive neuronal dysfunction and degeneration, ( ii ) expression of the disease phenotype when the size of the polyCAG/polyQ expansion reaches a precise threshold, which varies according to the gene, ( iii ) a strong negative correlation between age at onset and size of the polyQ tract, ( iv ) instability of the CAG repeat during transmission, with a strong tendency to expansion, resulting in an effect called anticipation (cf.…”

Section: Introductionmentioning

confidence: 99%

Requirement for Zebrafish Ataxin-7 in Differentiation of Photoreceptors and Cerebellar Neurons

et al. 2012

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The expansion of a polyglutamine (polyQ) tract in the N-terminal region of ataxin-7 (atxn7) is the causative event in spinocerebellar ataxia type 7 (SCA7), an autosomal dominant neurodegenerative disorder mainly characterized by progressive, selective loss of rod-cone photoreceptors and cerebellar Purkinje and granule cells. The molecular and cellular processes underlying this restricted neuronal vulnerability, which contrasts with the broad expression pattern of atxn7, remains one of the most enigmatic features of SCA7, and more generally of all polyQ disorders. To gain insight into this specific neuronal vulnerability and achieve a better understanding of atxn7 function, we carried out a functional analysis of this protein in the teleost fish Danio rerio. We characterized the zebrafish atxn7 gene and its transcription pattern, and by making use of morpholino-oligonucleotide-mediated gene inactivation, we analysed the phenotypes induced following mild or severe zebrafish atxn7 depletion. Severe or nearly complete zebrafish atxn7 loss-of-function markedly impaired embryonic development, leading to both early embryonic lethality and severely deformed embryos. More importantly, in relation to SCA7, moderate depletion of the protein specifically, albeit partially, prevented the differentiation of both retina photoreceptors and cerebellar Purkinje and granule cells. In addition, [1–232] human atxn7 fragment rescued these phenotypes showing strong function conservation of this protein through evolution. The specific requirement for zebrafish atxn7 in the proper differentiation of cerebellar neurons provides, to our knowledge, the first in vivo evidence of a direct functional relationship between atxn7 and the differentiation of Purkinje and granule cells, the most crucial neurons affected in SCA7 and most other polyQ-mediated SCAs. These findings further suggest that altered protein function may play a role in the pathophysiology of the disease, an important step toward the development of future therapeutic strategies.

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“…Spinocerebellar ataxia 7 (SCA7) is a late onset neurodegenerative disease which presents with a classic autosomal dominant ataxia but which is uniquely associated with macular degeneration [1]. It is part of a group of nine known polyglutamine (polyQ) disorders which share expanded (CAG) repeat mutations that translate into polyQ tracts [2].…”

Section: Introductionmentioning

confidence: 99%

Design of RNAi Hairpins for Mutation-Specific Silencing of Ataxin-7 and Correction of a SCA7 Phenotype

et al. 2009

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Spinocerebellar ataxia type 7 is a polyglutamine disorder caused by an expanded CAG repeat mutation that results in neurodegeneration. Since no treatment exists for this chronic disease, novel therapies such post-transcriptional RNA interference-based gene silencing are under investigation, in particular those that might enable constitutive and tissue-specific silencing, such as expressed hairpins. Given that this method of silencing can be abolished by the presence of nucleotide mismatches against the target RNA, we sought to identify expressed RNA hairpins selective for silencing the mutant ataxin-7 transcript using a linked SNP. By targeting both short and full-length tagged ataxin-7 sequences, we show that mutation-specific selectivity can be obtained with single nucleotide mismatches to the wild-type RNA target incorporated 3′ to the centre of the active strand of short hairpin RNAs. The activity of the most effective short hairpin RNA incorporating the nucleotide mismatch at position 16 was further studied in a heterozygous ataxin-7 disease model, demonstrating significantly reduced levels of toxic mutant ataxin-7 protein with decreased mutant protein aggregation and retention of normal wild-type protein in a non-aggregated diffuse cellular distribution. Allele-specific mutant ataxin7 silencing was also obtained with the use of primary microRNA mimics, the most highly effective construct also harbouring the single nucleotide mismatch at position 16, corroborating our earlier findings. Our data provide understanding of RNA interference guide strand anatomy optimised for the allele-specific silencing of a polyglutamine mutation linked SNP and give a basis for the use of allele-specific RNA interference as a viable therapeutic approach for spinocerebellar ataxia 7.

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On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family

Cited by 93 publications

References 22 publications

CTCF Regulates Ataxin-7 Expression through Promotion of a Convergently Transcribed, Antisense Noncoding RNA

CTCF Regulates Ataxin-7 Expression through Promotion of a Convergently Transcribed, Antisense Noncoding RNA

Requirement for Zebrafish Ataxin-7 in Differentiation of Photoreceptors and Cerebellar Neurons

Design of RNAi Hairpins for Mutation-Specific Silencing of Ataxin-7 and Correction of a SCA7 Phenotype

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