Recent Advances in the Genetics of Dystonia

Xiao, Jianfeng; Vemula, Satya R.; LeDoux, Mark S.

doi:10.1007/s11910-014-0462-8

Cited by 19 publications

(17 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because of the limited amounts of DNA available for this project (2 μg per participant) and questions related to the pathogenicity of CIZ1 and ANO3 SVs in participants with isolated dystonia, a combination of high-resolution melting (HRM) and Sanger sequencing was restricted to coding and contiguous noncoding regions of THAP1 , GNAL , and Exon 5 of TOR1A . 3 , 5 , 8 , 10 , 15 Exon 5 of TOR1A harbors the classic DYT1 ΔGAG mutation, and cosegregating pathogenic SVs have not been identified in other exons of TOR1A . 7 , 8 , 15 , 16 After the identification of 2 novel SVs in Exon 5 of TOR1A , an additional 1,160 DNA samples from the UTHSC Dystonia Genetics Consortium biorepository were also screened for these and other SVs within Exon 5 of TOR1A (table e-1 at Neurology.org/ng ).…”

Section: Methodsmentioning

confidence: 99%

Clinical and genetic features of cervical dystonia in a large multicenter cohort

et al. 2016

Self Cite

View full text Add to dashboard Cite

Objective:To characterize the clinical and genetic features of cervical dystonia (CD).Methods:Participants enrolled in the Dystonia Coalition biorepository (NCT01373424) with initial manifestation as CD were included in this study (n = 1,000). Data intake included demographics, family history, and the Global Dystonia Rating Scale. Participants were screened for sequence variants (SVs) in GNAL, THAP1, and Exon 5 of TOR1A.Results:The majority of participants were Caucasian (95%) and female (75%). The mean age at onset and disease duration were 45.5 ± 13.6 and 14.6 ± 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. The remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. Family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic SVs in THAP1, TOR1A, and GNAL were identified in 8 participants (0.8%). Two individuals harbored novel missense SVs in Exon 5 of TOR1A. Synonymous and noncoding SVs in THAP1 and GNAL were identified in 4% of the cohort.Conclusions:Head tremor, laryngeal dystonia, and psychiatric comorbidities are more common in female participants with CD. Coding and noncoding variants in GNAL, THAP1, and TOR1A make small contributions to the pathogenesis of CD.

show abstract

Section: Methodsmentioning

confidence: 99%

Clinical and genetic features of cervical dystonia in a large multicenter cohort

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…To date, >20 monogenic inherited dystonias and dystonia-related disorders (DYT1-25) have been reported in Online Mendelian Inheritance in Man (OMIM) (Xiao et al, 2014). Moreover, dystonia can also be a presenting or prominent clinical manifestation of numerous hereditary neurological diseases (LeDoux, 2012b).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, another missense variant (c.2357C > T, p.T786I) in CIZ1 was identified in a German patient of unknown family history (Dufke et al, 2015). Moreover, Exon 2 indels in CIZ1 may be enriched in subjects with dystonia in comparison to controls (Xiao et al, 2014, Dufke et al, 2015). However, neither nonsense nor large deletion mutations leading to haploinsufficiency have been identified in subjects with dystonia (Xiao et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, Exon 2 indels in CIZ1 may be enriched in subjects with dystonia in comparison to controls (Xiao et al, 2014, Dufke et al, 2015). However, neither nonsense nor large deletion mutations leading to haploinsufficiency have been identified in subjects with dystonia (Xiao et al, 2014). Therefore, the relative contributions of gain- or loss-of-function to the pathogenesis of CIZ1 -associated dystonia and cell-cycle control within the adult nervous system remain indeterminate (LeDoux et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

Xiao

Vemula

Xue

et al. 2016

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

A missense mutation in CIZ1 (c.790A > G, p.S264G) was linked to autosomal dominant cervical dystonia in a large multiplex Caucasian pedigree (OMIM614860, DYT23). CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein, widely expressed in neural and extra-neural tissues, and plays a role in DNA synthesis at the G1/S cell-cycle checkpoint. The role of CIZ1 in the nervous system and relative contributions of gain- or loss- of function to the pathogenesis of CIZ1-associated dystonia remain indefinite. Using relative quantitative reverse transcriptase-PCR, cerebellum showed the highest expression levels of Ciz1 in adult mouse brain, over two fold higher than liver, and higher than striatum, midbrain and cerebral cortex. Overall, neural expression of Ciz1 increased with postnatal age. A Ciz1 gene-trap knock-out (KO) mouse model (Ciz1−/−) was generated to examine the functional role(s) of CIZ1 in the sensorimotor nervous system and contributions of CIZ1 to cell-cycle control in the mammalian brain. Ciz1 transcripts were absent in Ciz1−/− mice and reduced by approximately 50% in Ciz1+/− mice. Ciz1−/− mice were fertile but smaller than wild-type (WT) littermates. Ciz1−/− mice did not manifest dystonia, but exhibited mild motoric abnormalities on balance, open-field activity, and gait. To determine the effects of germline KO of Ciz1 on whole-genome gene expression in adult brain, total RNA from mouse cerebellum was harvested from 6 10-month old Ciz1−/− mice and 6 age- and gender- matched WT littermates for whole-genome gene expression analysis. Based on whole-genome gene-expression analyses, genes involved in cellular movement, cell development, cellular growth, cellular morphology and cell-to-cell signaling and interaction were up-regulated in Ciz1−/− mice. The top up-regulated pathways were metabolic and cytokine-cytokine receptor interactions. Down-regulated genes were involved in cell cycle, cellular development, cell death and survival, gene expression and cell morphology. Down-regulated networks included those related to metabolism, focal adhesion, neuroactive ligand-receptor interaction, and MAPK signaling. Based on pathway analyses, transcription factor 7-like 2 (TCF7L2), a member of the Wnt/β-catenin signaling pathway, was a major hub for down-regulated genes, whereas NF-κB was a major hub for up-regulated genes. In aggregate, these data suggest that CIZ1 may be involved in the post-mitotic differentiation of neurons in response to external signals and changes in gene expression may compensate, in part, for CIZ1 deficiency in our Ciz1−/− mouse model. Although CIZ1 deficiency was associated with mild motor abnormalities, germline loss of Ciz1 was not associated with dystonia on the C57BL/6J background.

show abstract

“…A number of efforts have led to various classification systems of Dys, 4 – 8 attempts to characterize their biological bases, 9 – 13 and multiple proposals of clinical guidelines for their treatment. 14 – 16 However, although important progress has been achieved in understanding some of the neurological bases of Dys, especially in terms of molecular mechanisms 17 and genetic causes, 18 the distinct characteristic neuropathologic features of Dys remain poorly defined 19 with some very rare exceptions. 20 , 21 …”

Section: Introductionmentioning

confidence: 99%

Reduced Number of Pigmented Neurons in the Substantia Nigra of Dystonia Patients? Findings from Extensive Neuropathologic, Immunohistochemistry, and Quantitative Analyses

Iacono

Geraci-Erck

Peng

et al. 2015

Tremor and Other Hyperkinetic Movements

View full text Add to dashboard Cite

Recent Advances in the Genetics of Dystonia

Cited by 19 publications

References 69 publications

Clinical and genetic features of cervical dystonia in a large multicenter cohort

Clinical and genetic features of cervical dystonia in a large multicenter cohort

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

Reduced Number of Pigmented Neurons in the Substantia Nigra of Dystonia Patients? Findings from Extensive Neuropathologic, Immunohistochemistry, and Quantitative Analyses

Contact Info

Product

Resources

About