Refined Linkage Disequilibrium and Physical Mapping of the Gene Locus for X-Linked Dystonia–Parkinsonism (DYT3)

Németh, Andrea H.; Nolte, Dagmar; Dunne, Eimear; Niemann, Stephan; Kostrzewa, Markus; Peters, Usha; Fraser, Eileen; Bochukova, Elena G.; Butler, Robin; Brown, Julie; Cox, Roger D.; Levy, Elaine R.; Ropers, Hans‐Hilger; Monaco, Anthony P.; Müller, Ulrich

doi:10.1006/geno.1999.5929

Cited by 51 publications

(44 citation statements)

References 37 publications

(35 reference statements)

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“…In Amish-Mennonites with primary dystonia in whom the founder mutation in THAP1 has not been found, other variants in the same gene (but not the original indel), and in other genes for primary dystonia (GNAL and TOR1A) were later discovered to be causative for the phenotype. 22 Of note, in the original linkage study 3 and in the article that first described XDP-specific genetic variants, 7 there was also one patient who did not carry any of the genetic variants reported. This was, however, dismissed as a misdiagnosed case.…”

Section: Discussionmentioning

confidence: 99%

“…DXS10015 is excluded proximally, and DXS559 distally, from this haploblock, subtending a 427.4-kb region. Notably, these markers were reported by Németh et al 3 previously to include a 350-kb region, however, coordinates have since changed and using the current human genome assembly (GRCh38) calculates the included region to 427 kb.…”

Section: Sequencing Of Previously Described Genetic Variantsmentioning

confidence: 99%

“…Ninety-five percent of affected individuals are males; the average age is 44 years (20-70 years); and the average age at onset is 39 years (12-64 years). 2 The DYT3 disease locus has been mapped to an~427-kb region on Xq13.1 flanked by DXS10015 proximally and DXS559 distally, 3 however, previous studies did not reveal mutations in the coding regions of known genes inside this interval. [3][4][5][6] Instead, five disease-specific single-nucleotide changes (DSC1, DSC2, DSC3, DSC10, DSC12), one 48-bp deletion, and one 2627-bp SVA (SINE-VNTR-Alu element) retrotransposon insertion, all found either within 'deep intronic' or intergenic DNA segments, or in a nonconventional exon of the nearby TAF1 gene, have been identified only in affected individuals.…”

Section: Introductionmentioning

confidence: 99%

“…2 The DYT3 disease locus has been mapped to an~427-kb region on Xq13.1 flanked by DXS10015 proximally and DXS559 distally, 3 however, previous studies did not reveal mutations in the coding regions of known genes inside this interval. [3][4][5][6] Instead, five disease-specific single-nucleotide changes (DSC1, DSC2, DSC3, DSC10, DSC12), one 48-bp deletion, and one 2627-bp SVA (SINE-VNTR-Alu element) retrotransposon insertion, all found either within 'deep intronic' or intergenic DNA segments, or in a nonconventional exon of the nearby TAF1 gene, have been identified only in affected individuals. 7,8 None of these diseaseassociated genetic variants are located in protein-coding segments based on current annotations of the human genome, although the regulation of neuron-specific TAF1 isoforms or of other genes in the region has been postulated as disease mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Sequencing Of Previously Described Genetic Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Some lines of evidence suggest that the expression of Neuroligins may differ between species. For example, rat Neuroligin 3 is mainly detected in brain, whereas human Neuroligin 3 and 4 are also expressed in different peripheral tissues (Ichtchenko et al, 1996;Nemeth et al, 1999;Philibert et al, 2000;Bolliger et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the neuroligin gene family expression and evolution in zebrafish

Rissone¹,

Sangiorgio²,

Monopoli³

et al. 2010

Developmental Dynamics

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Neuroligins constitute a family of transmembrane proteins localized at the postsynaptic side of both excitatory and inhibitory synapses of the central nervous system. They are involved in synaptic function and maturation and recent studies have linked mutations in specific human Neuroligins to mental retardation and autism. We isolated the human Neuroligin homologs in Danio rerio. Next, we studied their gene structures and we reconstructed the evolution of the Neuroligin genes across vertebrate phyla. Using reverse-transcriptase polymerase chain reaction, we analyzed the expression and alternative splicing pattern of each gene during zebrafish embryonic development and in different adult organs. By in situ hybridization, we analyzed the temporal and spatial expression pattern during embryonic development and larval stages and we found that zebrafish Neuroligins are expressed throughout the nervous system. Globally, our results indicate that, during evolution, specific subfunctionalization events occurred within paralogous members of this gene family in zebrafish. Developmental Dynamics 239:688-702,

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Phenotypic and Molecular Analyses of X-linked Dystonia-Parkinsonism (“Lubag”) in Women

Evidente

Nolte²,

Niemann³

et al. 2004

Arch Neurol

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The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.

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Refined Linkage Disequilibrium and Physical Mapping of the Gene Locus for X-Linked Dystonia–Parkinsonism (DYT3)

Cited by 51 publications

References 37 publications

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

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

Characterization of the neuroligin gene family expression and evolution in zebrafish

Phenotypic and Molecular Analyses of X-linked Dystonia-Parkinsonism (“Lubag”) in Women

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