Biology subjects

Ozelius, L. J.

Publications and source records attributed to Ozelius, L. J..

5 recordsLinked to original sources

bioRxiv2026

What is pathogenicity? Structural vulnerabilities lead to distinct phenotypes in a membrane protein, ATP1A3

Distinct protein features of pathogenic variants are illustrated here for a gene with an extraordinarily wide range of neurological syndromes: ATP1A3, the neuronal Na,K-ATPase. Vulnerable structure features produce mechanistically different consequences, from loss or gain of function to maladaptive cell biological responses. Variants in specific structural elements (glycines, prolines, and {beta}-sheets) link severe phenotype to impaired folding during biosynthesis. In contrast, impaired protein-protein interactions may result in brain malformation. Defective RNA transcripts, on the other hand, exhibit a range of benign to severe phenotypes, likely due to efficacy variability in the defensive degradation of aberrant mRNA and protein. Variant interpretation will benefit from understanding structure-specific vulnerabilities.

neuroscience↗

bioRxiv2025

MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism

X-linked dystonia parkinsonism (XDP) is a progressive adult-onset neurogenerative disorder caused by the insertion of a SINE-VNTR-Alu (SVA) retrotransposon in TAF1 gene. One element of the SVA is a tandem polymorphic CCCTCT repeat tract whose length inversely correlates with the age of disease onset. Previous observations that the repeat exhibits length-dependent somatic expansion and that XDP onset is modified by variation in DNA repair gene MSH3 indicated that somatic repeat expansion is an important disease driver. Here, we sought to uncover genetic modifiers of CCCTCT instability in XDP patients and to provide a mechanistic link between somatic instability and disease. We determined quantitative metrics of both repeat expansion and repeat contraction in blood. Using genetic association analyses of exome sequencing data, as well as directed sequencing of a variant MSH3 repeat, we found that MSH3 modifies repeat expansion and contraction in blood as well as age at onset. MSH3 alleles associated with earlier disease onset were associated with more expansion and less contraction. Conversely, alleles associated with later disease onset were associated with less expansion and more contraction. Notably, MSH3 repeat alleles were also similarly associated with expansion and contraction in brain tissues. Our findings provide key evidence that MSH3s role(s) in CCCTCT repeat dynamics underlies its impact on clinical disease and indicate that therapeutic strategies to lower or inhibit MSH3 are predicted to both slow CCCTCT expansion and promote CCCTCT contraction, impacting the disease course prior to clinical onset.

genetics↗

bioRxiv2022

Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of [~]20->100 repeats and contractions of [~]20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntingtons disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

genetics↗

bioRxiv2021

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

Dystonia is a neurologic disorder associated with an increasingly large number of variants in many genes, resulting in characteristic disturbances in volitional movement. Dissecting the relationships between these mutations and their functional outcomes is a critical step in understanding the key pathways that drive dystonia pathogenesis. Here we established a pipeline for characterizing an allelic series of dystonia-specific mutations in isogenic induced pluripotent stem cells (iPSCs). We used this strategy to investigate the molecular consequences of variation in THAP1, which encodes a transcription factor that has been linked to neural differentiation. Multiple pathogenic mutations that have been associated with dystonia cluster within distinct THAP1 functional domains and are predicted to alter its DNA binding properties and/or protein interactions differently, yet the relative impact of these varied changes on molecular signatures and neural deficits is unclear. To determine the effects of these mutations on THAP1 transcriptional activity, we engineered an allelic series of eight mutations in a common iPSC background and differentiated these lines into a panel of near-isogenic neural stem cells (n = 94 lines). Transcriptome profiling of these neural derivatives followed by joint analysis of the most robust individual signatures across mutations identified a convergent pattern of dysregulated genes functionally related to neurodevelopment, lysosomal lipid metabolism, and myelin. Based on these observations, we examined mice bearing Thap1-disruptive alleles and detected significant changes in myelin gene expression and reduction of myelin structural integrity relative to tissue from control mice. These results suggest that deficits in neurodevelopment and myelination are common consequences of dystonia-associated THAP1 mutations and highlight the potential role of neuron-glial interactions in the pathogenesis of dystonia.

genetics↗

bioRxiv2017

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease endemic to the Philippines. We integrated genome and transcriptome assembly with induced pluripotent stem cell-based modeling to identify the XDP causal locus and potential pathogenic mechanism. Genome sequencing identified novel variation that was shared by all probands and three recombination events that narrowed the causal locus to a genomic segment including TAF1. Transcriptome assembly in neural derivative cells discovered novel TAF1 transcripts, including a truncated transcript exclusively observed in probands that involved aberrant splicing and intron retention (IR) associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion. This IR correlated with decreased expression of the predominant TAF1 transcript and altered expression of neurodevelopmental genes; both the IR and aberrant TAF1 expression patterns were rescued by CRISPR/Cas9 excision of the SVA. These data suggest a unique genomic cause of XDP and may provide a roadmap for integrative genomic studies in other unsolved Mendelian disorders.\n\nHighlights O_LIGenome assembly narrows the XDP causal locus to a segment including TAF1\nC_LIO_LIXDP-specific SVA insertion induces intron retention and down-regulation of TAF1\nC_LIO_LICRISPR/Cas9 excision of SVA rescues aberrant splicing and cTAF1 expression in XDP\nC_LIO_LIGene networks perturbed in proband cells associate to synapse and neurodevelopment\nC_LI

genomics↗