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Mafalda Raposo, Conceição Bettencourt, Patriıcia Maciel, Fuying Gao, Amanda Ramos, Nadiya Kazachkova, João Vasconcelos, Teresa Kay1, Ana João Rodrigues, Bruno Bettencourt, Jacome Bruges-Armas, Daniel Geschwind, Giovanni Coppola, Manuela Lima

1- Especialidade de Genética Médica, Área Departamental de Pediatria Médica, Hospital de Dona Estefânia, Centro Hospitalar de Lisboa Central, EPE

- Mov Disord. 2015 Jun;30(7):968-75. doi: 10.1002/mds.26238. Epub 2015 Apr 25.

Introduction: Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine
neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls,  we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status.
Methodology: The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real- time polymerase chain reaction (PCR).
Results and discussion: Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96);
FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls.
Conclusions: Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease

Key Words: spinocerebellar ataxia type 3; polyglutamine disease; gene expression; ataxin-3; microarray