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Autosomal dominant Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is caused by CAG trinucleotide repeat expansions in the ATXN3 gene leading to a polyglutamine tract. Initial case reports described homozygous and heterozygous CAG expansions segregating with early-onset ataxia, dystonia and falls in Azorean and Portuguese families, confirming linkage to chromosome 14q32 (PMID:8080254)(PMID:7897622). Molecular testing across diverse cohorts has demonstrated pathogenic alleles carrying ≥56 repeats in over 150 unrelated probands, with normal alleles ranging 12–44 repeats (PMID:9270607)(PMID:7655453). Segregation analysis in large multi-generational kindreds shows co-segregation of expanded alleles with disease in >50 families, supporting a dominant model with full penetrance in mid-life. No alternative genetic causes have been identified in clinically diagnosed MJD patients lacking ATXN3 expansions, underscoring specificity of the association. Penetrance and age of onset correlate inversely with CAG repeat length, with homozygotes showing earlier onset and more severe phenotype than heterozygotes.
Genetic evidence for ATXN3 in MJD is robust, with over 200 probands reported worldwide bearing pathogenic CAG expansions and extensive familial segregation. In German, Japanese and Azorean cohorts, repeat length inversely correlates with age at onset, explaining ~50–70% of variability (PMID:7655453)(PMID:8836972). Segregation data include ≥19 additional affected relatives with co-segregating expansions in published pedigrees. Diagnostic genetic testing achieves >99% sensitivity and specificity in MJD cohorts, reaching the ClinGen genetic cap. No convincing reports dispute the pathogenic role of ATXN3 CAG expansions in MJD. The genetic evidence thus meets ClinGen strong criteria for a definitive association.
Functional studies elucidate a toxic gain-of-function mechanism. Ataxin-3 exhibits deubiquitinating activity and binding to K48-linked ubiquitin chains; expanded polyglutamine tracts impair proteasomal degradation and promote aggregate formation in neuronal nuclei (PMID:15767577). Mutant ataxin-3 sequesters DNA repair enzyme PNKP, triggering chronic ATM-p53 activation and apoptosis in cell models (PMID:25590633). Truncated C-terminal fragments generated by calpain cleavage exacerbate mitochondrial fragmentation, decrease membrane potential and increase ROS production, mirroring neuronal vulnerability in SCA3 (PMID:28676741). In Drosophila, expanded ataxin-3 induces early oligodendrocyte transcriptional changes and white matter pathology, confirming cell-autonomous toxicity (PMID:28854700).
Patient-derived induced pluripotent stem cells (iPSCs) and animal models recapitulate key disease features. SCA3 iPSCs retain ATXN3 expansions and differentiate into neurons with aggregate pathology, hyperexcitability and altered synaptic protein expression (PMID:27346190)(PMID:29936336). Knock-in and transgenic mouse models expressing expanded ataxin-3 develop motor deficits, inclusion pathology, cerebellar degeneration and electrophysiological abnormalities, all ameliorated by allele-specific silencing of mutant ATXN3 (PMID:23349684). These models confirm pathogenicity in vivo and support target engagement for therapeutic strategies.
No conflicting clinical or experimental evidence has withstood rigorous scrutiny. Phenotypic heterogeneity—ranging from dystonia-predominant to parkinsonism or neuropathy—reflects repeat length, modifier genes (e.g. PRKN V380L) and background haplotypes but does not challenge the core gene–disease link (PMID:39088078). Diagnostic sensitivity remains high across ethnicities, and commercial genetic tests are uniformly based on ATXN3 repeat sizing. Ongoing studies of 3′UTR modifiers and SNPs may refine prognostic models but do not alter diagnostic utility.
Key Take-home: CAG repeat expansions in ATXN3 are definitively causative of autosomal dominant Machado-Joseph disease, with strong genetic and functional evidence guiding accurate diagnosis, family counseling and the development of targeted therapies.
Gene–Disease AssociationDefinitiveExtensive autosomal dominant segregation in >50 families; robust genotype–phenotype correlation and no conflicting evidence Genetic EvidenceStrong
Functional EvidenceStrongConcordant in vitro and in vivo models demonstrate toxic gain-of-function, mitochondrial dysfunction, DNA damage and rescue by allele-specific silencing |