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dc.contributor.authorGao, Yujing
dc.contributor.authorWilson, Gabrielle R
dc.contributor.authorSalce, Nicholas
dc.contributor.authorRomano, Alexandra
dc.contributor.authorMellick, George D
dc.contributor.authorStephenson, Sarah EM
dc.contributor.authorLockhart, Paul J
dc.date.accessioned2020-10-27T04:00:38Z
dc.date.available2020-10-27T04:00:38Z
dc.date.issued2020
dc.identifier.issn1664-2295
dc.identifier.doi10.3389/fneur.2020.00523
dc.identifier.urihttp://hdl.handle.net/10072/398758
dc.description.abstractPathogenic variants in the gene encoding RAB39B, resulting in the loss of protein function, lead to the development of X-linked early-onset parkinsonism. The gene is located within a chromosomal region that is susceptible to genomic rearrangement, and while an increased dosage of RAB39B was previously associated with cognitive impairment, the potential role of dosage alterations in Parkinson's disease (PD) remains to be determined. This study aimed to investigate the contribution of the genetic variation in RAB39B to the development of early-onset PD. We performed gene dosage studies and sequence analysis in a cohort of 176 individuals with early-onset PD (age of onset ≤ 50 years) of unknown genetic etiology. An assessment of the copy number variation over both coding exons and the 3' untranslated region (UTR) of RAB39B did not identify any alterations in gene dosage. An analysis of the UTRs identified two male individuals carrying single, likely benign, nucleotide variants in the 3'UTR (chrX:154489749-A-G and chrX:154489197-T-G). Furthermore, one novel variant of uncertain significance was identified in the 5'UTR, 229 bp upstream of the start codon (chrX:154493802-C-T). In silico analyses predicted that this variant disrupts a highly conserved transcription factor binding site and could impact RAB39B expression. The results of this study do not support a significant role for genetic variation in RAB39B as contributing to early-onset PD but do highlight that additional molecular studies are required to determine the mechanisms regulating RAB39B expression and their association with the disease. Genetic investigations in larger parkinsonism/PD cohorts and longitudinal studies of individuals with cognitive impairment due to an altered dosage of RAB39B will be required to fully delineate the contribution of RAB39B to parkinsonism.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherFrontiers Media SA
dc.relation.ispartofpagefrom523
dc.relation.ispartofjournalFrontiers in Neurology
dc.relation.ispartofvolume11
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchNeurosciences
dc.subject.fieldofresearchPsychology
dc.subject.fieldofresearchcode1103
dc.subject.fieldofresearchcode1109
dc.subject.fieldofresearchcode1701
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsClinical Neurology
dc.subject.keywordsNeurology
dc.titleGenetic Analysis ofRAB39Bin an Early-Onset Parkinson's Disease Cohort
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationGao, Y; Wilson, GR; Salce, N; Romano, A; Mellick, GD; Stephenson, SEM; Lockhart, PJ, Genetic Analysis ofRAB39Bin an Early-Onset Parkinson's Disease Cohort, Frontiers in Neurology, 2020, 11, pp. 523
dcterms.dateAccepted2020-05-12
dc.date.updated2020-10-27T03:57:41Z
dc.description.versionVersion of Record (VoR)
gro.hasfulltextFull Text
gro.griffith.authorMellick, George


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