Improvement in the Molecular Diagnosis of Machado-Joseph Disease

Maciel, Patrı́cia; Costa, Maria do Carmo; Ferro, Anabela; Rousseau, Marylène; Santos, Célia; Gaspar, Cláudia; Barros, José; Rouleau, Guy A.; Coutinho, Paula; Sequeiros, Jorge

doi:10.1001/archneur.58.11.1821

Cited by 123 publications

(101 citation statements)

References 37 publications

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“…At the amino acid level, mouse ataxin-3 revealed 94 and 82-86% identity with rat and human proteins, respectively. The (CAG) n repeat in the mouse Mjd gene, as well as in the rat gene [29], is shorter than in its human counterpart, containing 6 triplet units compared to the range of 10-51 repeats in the normal human population [12,13]. Reduced length of polyglutamine tracts and high conservation at the amino acid level have also been observed Analysis of the 1173-bp regulating region upstream of mouse Mjd revealed the presence of putative binding sites for the transcription factors Sp1, USF, Max, Arnt, E47 and MyoD, which were conserved in the 5′ flanking region of the human gene, and the presence of potential binding sites for GATA-4, Nkx-2.5, myogenin, MEF-2, c-Myb, AP-2α, RAR-γ/ RXR-β, N-Oct-3, Sox-5, GR, AP1, and MAZ.…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

“…The minimal poly(Q) length to cause disease is variable among these disorders. The CAG repeat tract in MJD contains 10-51 triplets in healthy individuals and 55-87 in patients [12,13].…”

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confidence: 99%

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Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

et al. 2004

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Machado-Joseph disease (MJD) is a neurodegenerative disorder, caused by the expansion of the (CAG) n tract in the MJD gene. This encodes the protein ataxin-3, of unknown function. The mouse Mjd gene has a structure similar to that of its human counterpart and it also contains a TATA-less promoter. Its 5′ flanking region contains conserved putative binding regions for transcription factors Sp1, USF, Arnt, Max, E47, and MyoD. Upon differentiation of P19 cells, the Mjd gene promoter is preferentially activated in endodermal and mesodermal derivatives, including cardiac and skeletal myocytes; and less so in neuronal precursors. Mouse ataxin-3 is ubiquitously expressed during embryonic development and in the adult, with strong expression in regions of the CNS affected in MJD. It is particularly abundant in all types of muscle and in ciliated epithelial cells, suggesting that it may be associated with the cytoskeleton and may have an important function in cell structure and/or motility. KeywordsAtaxin-3; Polyglutamine; Spinocerebellar ataxia; Triplet repeat; Muscle; Myocytes; MyoD; E47; Max; Arnt Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a neurodegenerative disorder of late onset and the most common dominant spinocerebellar ataxia worldwide (30% among all forms) [1]. Patients present with cerebellar ataxia and ☆ Supplementary data for this article may be found on ScienceDirect. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptprogressive external ophthalmoplegia, associated in a variable degree with pyramidal signs, extrapyramidal signs (dystonia or rigidity), amyotrophy, and peripheral neuropathy [2]. Pathologically, MJD is characterized by neuronal loss in the spinocerebellar, dentate, pontine, and vestibular nuclei, the substantia nigra, the locus coeruleus, the palidoluysian complex, the motor cranial nerve and medulla anterior horn nuclei, and the dorsal root ganglia [2][3][4].The MJD causative gene was mapped to chromosome 14q32.1 in 1993 [5] and cloned in 1994 [6], but its structure has only recently been elucidated [7]. Alternative splicing of MJD results in the production of different isoforms of ataxin-3 [8], which are expressed in various tissues and have been detected both in the nucleus and in the cytoplasm [7,[9][10][11]. MJD is one of the CAG repeat/polyglutamine disorders, which includes Huntington disease (HD), spinal and bulbar muscular atrophy, dentatorubropallidoluysian atrophy (DRPLA), and other spinocerebellar ataxias, such as SCA1, 2, 6, 7, 12, and 17 [19,20], while inhibition of the proteasome pathway enhances cell death [21,22]. Another hypothesis for the mechanism of neurodegeneration is the possibility of amyloid formation, as in Alzheimer disease and other neurodegenerative disorders, but with a different subcellular location [23]. Infrared spectroscopy measurements have shown that ataxin-3, containing an expanded poly(Q) tract, also forms fibrils in vitro presenting a higher content of β sheets [24]. There is evidence ...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

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Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

et al. 2004

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“…4A). In addition, they displayed abnormalities in their swimming movements, adopting a twisted posture, and kicked in an uncoordinated (2), limb clasping (4) and reduced hindlimb tonus (6) in comparison with wt animals (1,3,5). (E) Assessment of body weight with age (n=11-12 for each group).…”

Section: Cmvmjd135 Transgenic Mice Display Progressive Neurological Dmentioning

confidence: 99%

“…Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is caused by a CAG repeat expansion (>55) [1] in the protein coding region of the ATXN3 gene, located in chromosome 14q32.1 and encoding the protein ataxin-3. The main clinical features of MJD are ataxia and ophthalmoplegia, which can be associated to a variable degree with peripheral amyotrophy, intention fasciculation-like movements of facial and lingual muscles, rigidity, spasticity, dystonia and palpebral retraction, leading to the appearance of bulging eyes [2].…”

Section: Introductionmentioning

confidence: 99%

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

et al. 2014

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Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein.Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD.

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Asian Origin for the Worldwide-Spread Mutational Event in Machado-Joseph Disease

Martins¹,

Calafell²,

Gaspar³

et al. 2007

Arch Neurol

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Background: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.Objectives: To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations.Design, Setting, and Participants: We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage. Results:The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774±1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93). Conclusions:The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416±434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.

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Improvement in the Molecular Diagnosis of Machado-Joseph Disease

Abstract: We propose an improved protocol for molecular testing for MJD. These strategies, developed to overcome the practical difficulties mostly in the presymptomatic and prenatal diagnosis of MJD, should prove useful for other polyglutamine-related disorders.

Cited by 123 publications

References 37 publications

Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Asian Origin for the Worldwide-Spread Mutational Event in Machado-Joseph Disease

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