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  • 1
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    A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism
    Wiley ; 2019
    In:  Annals of Neurology Vol. 85, No. 6 ( 2019-06), p. 812-822
    Details
    In: Annals of Neurology, Wiley, Vol. 85, No. 6 ( 2019-06), p. 812-822
    Abstract: X‐linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE‐VNTR‐Alu (SVA) retrotransposon insertion in TAF1 . Recently, a (CCCTCT) n repeat within the SVA insertion has been reported as an age‐at‐onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. Methods We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. Results RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. Interpretation The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN‐dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812–822.
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v85.6
    DOI: 10.1002/ana.25488
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2037912-2
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  • 2
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    DNA Methylation as a Potential Molecular Mechanism in X‐linked Dystonia‐Parkinsonism
    Wiley ; 2020
    In:  Movement Disorders Vol. 35, No. 12 ( 2020-12), p. 2220-2229
    Details
    In: Movement Disorders, Wiley, Vol. 35, No. 12 ( 2020-12), p. 2220-2229
    Abstract: X‐linked dystonia‐parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X‐linked dystonia‐parkinsonism, 3 disease‐specific single‐nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X‐linked dystonia‐parkinsonism. Methods DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell–derived cortical neurons and brain tissue from X‐linked dystonia‐parkinsonism patients and age‐ and sex‐matched healthy Filipino controls in a prospective study. Results Compared with controls, X‐linked dystonia‐parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation‐sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA–protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding. Conclusions We identified altered DNA methylation in X‐linked dystonia‐parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation‐modifying agents. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v35.12
    DOI: 10.1002/mds.28239
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2041249-6
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  • 3
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    Mutations in TUBB4A and spastic paraplegia
    Wiley ; 2015
    In:  Movement Disorders Vol. 30, No. 13 ( 2015-11), p. 1857-1858
    Details
    In: Movement Disorders, Wiley, Vol. 30, No. 13 ( 2015-11), p. 1857-1858
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v30.13
    DOI: 10.1002/mds.26444
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2041249-6
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  • 4
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    Familial Cerebellar Ataxia and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia with DAB1 and C9ORF72 Repeat Expansions: An 18‐Year Study
    Wiley ; 2022
    In:  Movement Disorders Vol. 37, No. 12 ( 2022-12), p. 2427-2439
    Details
    In: Movement Disorders, Wiley, Vol. 37, No. 12 ( 2022-12), p. 2427-2439
    Abstract: Coding and noncoding repeat expansions are an important cause of neurodegenerative diseases. Objective This study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co‐occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short‐read genome sequencing, long‐read sequencing, repeat‐primed polymerase chain reaction, and Southern blotting. Results The family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1 ‐related ataxia (ATX‐DAB1; SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT] ≈75 [ATTTC] ≈40‐100 [ATTTT] ≈415 ). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection. Conclusion We demonstrate genetic and clinical findings during an 18‐year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v37.12
    DOI: 10.1002/mds.29221
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 5
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    The New p. F1700L LRRK2 Variant Causes Parkinson's Disease by Extensively Increasing Kinase Activity
    Wiley ; 2023
    In:  Movement Disorders Vol. 38, No. 6 ( 2023-06), p. 1105-1107
    Details
    In: Movement Disorders, Wiley, Vol. 38, No. 6 ( 2023-06), p. 1105-1107
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v38.6
    DOI: 10.1002/mds.29385
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 6
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    Improving analysis of the vaginal microbiota of women undergoing assisted reproduction using nanopore sequencing
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Assisted Reproduction and Genetics Vol. 39, No. 11 ( 2022-11), p. 2659-2667
    Details
    In: Journal of Assisted Reproduction and Genetics, Springer Science and Business Media LLC, Vol. 39, No. 11 ( 2022-11), p. 2659-2667
    Abstract: Subclinical alterations of the vaginal microbiome have been described to be associated with female infertility and may serve as predictors for failure of in vitro fertilization treatment. While large prospective studies to delineate the role of microbial composition are warranted, integrating microbiome information into clinical management depends on economical and practical feasibility, specifically on a short duration from sampling to final results. The currently most used method for microbiota analysis is either metagenomics sequencing or amplicon-based microbiota analysis using second-generation methods such as sequencing-by-synthesis approaches (Illumina), which is both expensive and time-consuming. Thus, additional approaches are warranted to accelerate the usability of the microbiome as a marker in clinical praxis. Methods Herein, we used a set of ten selected vaginal swabs from women undergoing assisted reproduction, comparing and performing critical optimization of nanopore-based microbiota analysis with the results from MiSeq-based data as a quality reference. Results The analyzed samples carried varying community compositions, as shown by amplicon-based analysis of the V3V4 region of the bacterial 16S rRNA gene by MiSeq sequencing. Using a stepwise procedure to optimize adaptation, we show that a close approximation of the microbial composition can be achieved within a reduced time frame and at a minimum of costs using nanopore sequencing. Conclusions Our work highlights the potential of a nanopore-based methodical setup to support the feasibility of interventional studies and contribute to the development of microbiome-based clinical decision-making in assisted reproduction.
    Type of Medium: Online Resource
    ISSN: 1058-0468 , 1573-7330
    URL: Article
    DOI: 10.1007/s10815-022-02628-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2016722-2
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  • 7
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    Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 3 ( 2023-03-01), p. 1075-1082
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 3 ( 2023-03-01), p. 1075-1082
    Abstract: While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5′-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5′-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5′-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] , at median frequencies of 0.425 (IQR: 0.42–0.43) and 0.128 (IQR: 0.12–0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = −3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = −41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = −161.09, P = 3.44 × 10−5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = −92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac160
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 8
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    Genotype‐phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review
    Wiley ; 2018
    In:  Movement Disorders Vol. 33, No. 12 ( 2018-12), p. 1857-1870
    Details
    In: Movement Disorders, Wiley, Vol. 33, No. 12 ( 2018-12), p. 1857-1870
    Abstract: This comprehensive MDSGene review is devoted to the three autosomal‐dominant PD forms: PARK‐ SNCA , PARK‐ LRRK2 , and PARK‐ VPS35 . It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2 , or VPS35 . All of these data are also available in an easily searchable online database ( www.mdsgene.org ), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 ( P   〈  0.001). SNCA mutation carriers often have additional psychiatric symptoms, and although not exclusive to only LRRK2 or VPS35 mutation carriers, LRRK2 mutation carriers have a typical form of PD, and, lastly, VPS35 mutation carriers have good response to l ‐dopa. © 2018 International Parkinson and Movement Disorder Society
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v33.12
    DOI: 10.1002/mds.27527
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2041249-6
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  • 9
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    Genotype–Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review
    Wiley ; 2021
    In:  Movement Disorders Vol. 36, No. 11 ( 2021-11), p. 2468-2480
    Details
    In: Movement Disorders, Wiley, Vol. 36, No. 11 ( 2021-11), p. 2468-2480
    Abstract: This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet‐derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet‐derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis‐regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one‐third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants ( 〈 70%) was lower in comparison to the remaining three genes ( 〉 85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal‐dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype–phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v36.11
    DOI: 10.1002/mds.28753
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 10
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    DataSheet2.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Genetics Vol. 13 ( 2022-5-19)
    Details
    In: Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2022-5-19)
    Abstract: Background: Sequencing quality has improved over the last decade for long-reads, allowing for more accurate detection of somatic low-frequency variants. In this study, we used mixtures of mitochondrial samples with different haplogroups (i.e., a specific set of mitochondrial variants) to investigate the applicability of nanopore sequencing for low-frequency single nucleotide variant detection. Methods: We investigated the impact of base-calling, alignment/mapping, quality control steps, and variant calling by comparing the results to a previously derived short-read gold standard generated on the Illumina NextSeq. For nanopore sequencing, six mixtures of four different haplotypes were prepared, allowing us to reliably check for expected variants at the predefined 5%, 2%, and 1% mixture levels. We used two different versions of Guppy for base-calling, two aligners (i.e., Minimap2 and Ngmlr), and three variant callers (i.e., Mutserve2, Freebayes, and Nanopanel2) to compare low-frequency variants. We used F 1 score measurements to assess the performance of variant calling. Results: We observed a mean read length of 11 kb and a mean overall read quality of 15. Ngmlr showed not only higher F 1 scores but also higher allele frequencies (AF) of false-positive calls across the mixtures (mean F 1 score = 0.83; false-positive allele frequencies & lt; 0.17) compared to Minimap2 (mean F 1 score = 0.82; false-positive AF & lt; 0.06). Mutserve2 had the highest F 1 scores (5% level: F 1 score & gt;0.99, 2% level: F 1 score & gt;0.54, and 1% level: F 1 score & gt;0.70) across all callers and mixture levels. Conclusion: We here present the benchmarking for low-frequency variant calling with nanopore sequencing by identifying current limitations.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fgene.2022.887644
    DOI: 10.3389/fgene.2022.887644.s001
    DOI: 10.3389/fgene.2022.887644.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606823-0
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