Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia

Walter, Martín; Bonin, Michael; Pullman, Rachel Saunders; Valente, Enza Maria; Loi, Mario; Gambarin, Mattia; Raymond, Deborah; Tinazzi, Michèle; Kamm, Christoph; Glöckle, Nicola; Poths, Sven; Gasser, Thomas; Bressman, Susan; Klein, Christine; Ozelius, Laurie J.; Rieß, Olaf; Grundmann, Kathrin

doi:10.1016/j.nbd.2009.12.019

Cited by 19 publications

(13 citation statements)

References 51 publications

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“…Efforts to characterize DYT1-related molecular signatures in cultured cells (Baptista et al, 2003; Martin et al, 2009) or mouse models (Grundmann et al, 2008) have detected only modest transcriptional changes. However, recent profiling in blood of DYT1 individuals relative to controls revealed a signature that appeared to correlate with clinical disease penetrance (Walter et al 2010). …”

Section: Transcriptional Regulationmentioning

confidence: 99%

Molecular pathways in dystonia

Bragg

Armata

Nery

et al. 2011

Neurobiology of Disease

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The hereditary dystonias comprise a set of diseases defined by a common constellation of motor deficits. These disorders are most likely associated with different molecular etiologies, many of which have yet to be elucidated. Here we discuss recent advances in three forms of hereditary dystonia, DYT1, DYT6 and DYT16, which share a similar clinical picture: onset in childhood or adolescence, progressive spread of symptoms with generalized involvement of body regions and a steady state affliction without treatment. Unlike DYT1, the genes responsible for DYT6 and DYT16 have only recently been identified, with relatively little information about the function of the encoded proteins. Nevertheless, recent data suggest that these proteins may fit together within interacting pathways involved in dopaminergic signaling, transcriptional regulation, and cellular stress responses. This review focuses on these molecular pathways, highlighting potential common themes among these dystonias which may serve as areas for future research.

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Section: Transcriptional Regulationmentioning

confidence: 99%

Molecular pathways in dystonia

Bragg

Armata

Nery

et al. 2011

Neurobiology of Disease

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“…Moreover, the effects of the TT variant on overall gene expression (transcript) were interrogated in leukocytes and replicated in lymphoblastoid cell lines (transcript and protein) derived from distinct cohorts of cases and controls. Although RNA derived from peripheral blood has been used to study DYT1 dystonia9 and other movement disorders, analysis of gene expression in lymphoblastoid cell lines limits potential exogenous confounds including the effects of medications, nutrient intake, and concomitant infectious and inflammatory medical conditions.…”

mentioning

confidence: 99%

The c.‐237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia

Xiao¹,

Zhao²,

Bastian³

et al. 2011

Movement Disorders

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Sequence variants in coding and non-coding regions of THAP1 have been associated with primary dystonia. In this study, 1446 Caucasian subjects with mainly adult-onset primary dystonia and 1520 controls were genotyped for a variant located in the 5'-untranslated region of THAP1 (c.-237_236GA>TT). Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P = 0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein. Our DYT6 dystonia is an autosomal dominant primary dystonia causally-associated with sequence variants in THAP1 which encodes the DNA-binding transcription factor THAP1.1 -3 DYT6 dystonia shows reduced penetrance and variable expressivity.2 -8 In contrast to DYT1 dystonia, DYT6 more commonly remains focal in distribution and often affects the cervical and laryngeal musculature.1 , 4 , 5 Over 30 sequence variants have been localized to the coding regions of THAP1 and associated with focal, segmental, multi-focal or generalized dystonia with age of onset ranging from 2 to 62 years.1 -8 In addition, several asymptomatic carriers have been identified in the relatives of probands. The genetic and phenotypic heterogeneity of DYT6 dystonia, and variable penetrance of known coding variants suggest that non-coding variants in THAP1 could contribute to the risk of developing adult-onset primary dystonia.4 , 5 , 7 Given that THAP1 is a transcriptional repressor, it is conceivable that non-coding variants which cause minor quantitative changes in the temporal or spatial patterns of THAP1 expression could have broad effects on the transcriptome.Djarmati and colleagues4 identified a non-coding sequence variant (c.-237_236GA>TT) near the transcriptional start site of THAP1 that might increase the risk of developing primary dystonia. The relative frequency of this polymorphism in their subjects with dystonia (20/320) relative to controls (7/355) was noteworthy (P = 0.0054). Extrapolation of their findings to a broad population of late-onset primary dystonia is problematic given that the subjects with dystonia were relatively young (mean age of onset = 38.5 years) and predominantly Northern German whereas the control group was composed of Caucasian individuals of more diverse European ancestry. Another, relatively small case-control study with heterogeneous control and dystonia populations did not find an association between the TT allele and risk for dystonia.7Herein, we present the results of a large case-control study of c.-237_236GA>TT in primary, mainly adult-onset, dystonia. All subjects were Caucasians. Moreover, the effects of the TT variant on overall gene expression (transcript) were interrogated in leukocytes, and replicated in lymphoblastoid cell lines (transcript and protein) derived from distinct cohorts of cases and controls. Although RNA derived from peripheral blood has been us...

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“…Recently, several studies based on neuroimaging, neurophysiological, and expression profiling approaches have reported subclinical abnormalities (endophenotypes) in healthy DYT1/DYT6 mutation carriers (Fiorio et al, 2007; Bradley et al, 2009; Walter et al, 2010; Niethammer et al, 2011; Phukan et al, 2011). For instance, magnetic resonance diffusion tensor imaging used in conjunction with probabilistic tractography have demonstrated an anatomical disruption of cerebellar outflow in all DYT1/DYT6 carriers regardless of the phenotype, while a second protective downstream alteration of thalamo-cortical projections was found in non-manifesting carriers only (Argyelan et al, 2009).…”

Section: New Approaches To Improve Knowledge On Ptd Geneticsmentioning

confidence: 99%

Genetic Issues in the Diagnosis of Dystonias

Petrucci¹,

Valente²

2013

Front. Neurol.

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Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting and repetitive movements and abnormal postures. Several causative genes have been identified, but their genetic bases still remain elusive. Primary Torsion Dystonias (PTDs), in which dystonia is the only clinical sign, can be inherited in a monogenic fashion, and many genes and loci have been identified for autosomal dominant (DYT1/TOR1A; DYT6/THAP1; DYT4/TUBB4a; DYT7; DYT13; DYT21; DYT23/CIZ1; DYT24/ANO3; DYT25/GNAL) and recessive (DYT2; DYT17) forms. However most sporadic cases, especially those with late-onset, are likely multifactorial, with genetic and environmental factors interplaying to reach a threshold of disease. At present, genetic counseling of dystonia patients remains a difficult task. Recently non-motor clinical findings in dystonias, new highlights in the pathophysiology of the disease, and the availability of high-throughput genome-wide techniques are proving useful tools to better understand the complexity of PTD genetics. We briefly review the genetic basis of the most common forms of hereditary PTDs, and discuss relevant issues related to molecular diagnosis and genetic counseling.

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Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia

Cited by 19 publications

References 51 publications

Molecular pathways in dystonia

Molecular pathways in dystonia

The c.‐237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia

Genetic Issues in the Diagnosis of Dystonias

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