Application of long-range polymerase chain reaction in the diagnosis of X-linked dystonia–parkinsonism

Kawarai, Toshitaka; Pasco, Paul Matthew D.; Teleg, Rosalia A.; Kamada, Masaki; Sakai, Waka; Shimozono, Komei; Mizuguchi, Makoto; Tabuena, Daisy; Orlacchio, Antonio; Izumi, Yuishin; Goto, Satoshi; Lee, Lillian V.; Kaji, Ryuji

doi:10.1007/s10048-013-0357-x

Cited by 17 publications

(19 citation statements)

References 5 publications

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“…An in-house local variant database was also used, which consists of data derived from 106 control exome experiments. To validate the presence of the candidate variations in controls, 230 healthy individuals (200 Japanese and 30 Italian) were recruited for Sanger sequencing, as described elsewhere 26. Missense variants were analysed with PolyPhen-2, SIFT, MutationTaster and PROVEAN, to predict the pathological features of single amino acid mutations 27–30.…”

Section: Methodsmentioning

confidence: 99%

A homozygous mutation ofVWA3Bcauses cerebellar ataxia with intellectual disability

Kawarai

Tajima

Kuroda

et al. 2015

J Neurol Neurosurg Psychiatry

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Section: Methodsmentioning

confidence: 99%

A homozygous mutation ofVWA3Bcauses cerebellar ataxia with intellectual disability

Kawarai

Tajima

Kuroda

et al. 2015

J Neurol Neurosurg Psychiatry

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“…[8][9][10] The number of the (CCCTCT) n repeat was determined in DNA derived from (1) blood of 420 TAF1 SVA insertion carriers; (2) brain tissue (basal ganglia, cerebellum, midbrain, cortex) of 2 deceased XDP patients; and (3) fibroblasts, iPSCs, and iPSC-derived cortical neurons and MSNs from 13 patients. [8][9][10] The number of the (CCCTCT) n repeat was determined in DNA derived from (1) blood of 420 TAF1 SVA insertion carriers; (2) brain tissue (basal ganglia, cerebellum, midbrain, cortex) of 2 deceased XDP patients; and (3) fibroblasts, iPSCs, and iPSC-derived cortical neurons and MSNs from 13 patients.…”

Section: Genetic Analysesmentioning

confidence: 99%

“…9 The PCR product was subsequently digested with BsaI, HindIII, HaeIII, and MseI enzymes, and the SVA repeat region and surrounding base pairs were included in a 458 + (n × 6) bp fragment (n = number of repeats). Briefly, a very small amount of DNA (75 pg) corresponding to the quantity of DNA in only 1 to 2 cells was added to the PCR reaction amplifying the entire SVA insertion.…”

Section: Genetic Analysesmentioning

confidence: 99%

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

Westenberger

Reyes

Saranza

et al. 2019

Annals of Neurology

114

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Objective: 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.

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“…15 Haplotype analysis using STR markers within or surrounding the disease locus (DXS10015, DXS10016, DXS10017, DXS10018, and DXS559) 7 were analyzed on polyacrylamide gels or on an ABI3130XL Genetic Analyzer running GeneMapper 4.0 software (Applied Biosystems). Primer sequences and conditions are available upon request.…”

Section: Sanger Sequencing and Short Tandem Repeat (Str) Polymorphismmentioning

confidence: 99%

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3)

Domingo

Westenberger

Lee³

et al. 2015

Eur J Hum Genet

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X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.

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Application of long-range polymerase chain reaction in the diagnosis of X-linked dystonia–parkinsonism

Cited by 17 publications

References 5 publications

A homozygous mutation ofVWA3Bcauses cerebellar ataxia with intellectual disability

A homozygous mutation ofVWA3Bcauses cerebellar ataxia with intellectual disability

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3)

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