The human MJD gene: genomic structure and functional characterization of the promoter region

Schmitt, Imke; Evert, Bernd O.; Khazneh, Hassan; Klockgether, Thomas; Wuellner, Ullrich

doi:10.1016/s0378-1119(03)00706-6

Cited by 17 publications

(20 citation statements)

References 28 publications

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“…Previous studies from the PACE consortium have used a similar methodology to prescribe cohort-specific analyzes and to meta-analyze results from several cohorts. These studies identified many, seemingly robust, associations [22,[65][66]. This suggests that the lack of associations identified in our study is not likely due to poor EWAS or meta-analysis methodology or data.…”

Section: Discussionsupporting

confidence: 47%

“…Two large CpG islands are found in the promoter region (from -1089 to +1) of the ATXN3 gene [66], with the methylation levels in the first CpG island being significantly increased in SCA3/MJD patients and the second CpG island being hypomethylated in both patients and controls, suggesting an essential role of the first but not the second island DNA methylation in the SCA3 pathogenesis [67]. Genome-wide methylation analysis shows that ATXN2 is significantly methylated in a case series of coronary artery disease [68].…”

Section: Alteration Of Methylation In Scasmentioning

confidence: 99%

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Welcome to the 10th volume of Epigenomics

Martin

2017

Epigenomics

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Section: Discussionsupporting

confidence: 47%

Section: Alteration Of Methylation In Scasmentioning

confidence: 99%

Welcome to the 10th volume of Epigenomics

Martin

2017

Epigenomics

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“…The 5’-flanking region is a TATA-less promoter, comprising GC-rich regions, a CCAAT box, multiple putative SP1 binding sites, and a core promoter region within ~300 bp of the start codon (Schmitt et al , 2003). The ATXN3 3’ untranslated region (UTR) remains unstudied but the existence of transcripts carrying different 3’UTRs suggests additional gene regulation at this level (Ichikawa et al , 2001).…”

Section: The Disease Gene Atxn3mentioning

confidence: 99%

Toward understanding Machado–Joseph disease

Costa

Paulson

2012

Progress in Neurobiology

239

236

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Machado-Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.

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“…This 11 exon gene encodes the disease protein ataxin-3, also known as MJDp (Ichikawa et al, 2001; Schmitt et al, 2003). The CAG repeat resides in the 10 th exon, where it encodes a polyglutamine tract near the carboxyl terminus of this ~ 42 kilodalton protein.…”

Section: Genetic Featuresmentioning

confidence: 99%

Machado–Joseph disease/spinocerebellar ataxia type 3

Paulson

2012

Handbook of Clinical Neurology

160

137

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Machado Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light to what is known about the entire class of polyglutamine diseases.

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The human MJD gene: genomic structure and functional characterization of the promoter region

Cited by 17 publications

References 28 publications

Welcome to the 10th volume of Epigenomics

Welcome to the 10th volume of Epigenomics

Toward understanding Machado–Joseph disease

Machado–Joseph disease/spinocerebellar ataxia type 3

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