Loss-of-function mutations in SGCE, which encodes ε-sarcoglycan (ε-SG), cause myoclonus-dystonia syndrome (OMIM159900, DYT11). A "major" ε-SG protein derived from CCDS5637.1 (NM_003919.
View Article and Find Full Text PDFA missense mutation in CIZ1 (c.790A>G, p.S264G) was linked to autosomal dominant cervical dystonia in a large multiplex Caucasian pedigree (OMIM614860, DYT23).
View Article and Find Full Text PDFObjective: 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.
Background: Isolated blepharospasm (BSP) is a late-onset focal dystonia characterized by involuntary contractions of the orbicularis oculi muscles. Genetic studies of BSP have been limited by the paucity of large multiplex pedigrees. Although sequence variants (SVs) in THAP1 have been reported in rare cases of BSP, the genetic causes of this focal dystonia remain largely unknown.
View Article and Find Full Text PDFDystonia, a common and genetically heterogeneous neurological disorder, was recently defined as "a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both." Via the application of whole-exome sequencing, the genetic landscape of dystonia and closely related movement disorders is becoming exposed. In particular, several "novel" genetic causes have been causally associated with dystonia or dystonia-related disorders over the past 2 years.
View Article and Find Full Text PDFAlthough coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986).
View Article and Find Full Text PDFObjective: To determine the contribution of TUBB4A, recently associated with DYT4 dystonia in a pedigree with "whispering dysphonia" from Norfolk, United Kingdom, to the etiopathogenesis of primary dystonia.
Methods: High-resolution melting and Sanger sequencing were used to inspect the entire coding region of TUBB4A in 575 subjects with primary laryngeal, segmental, or generalized dystonia.
Results: No pathogenic variants, including the exon 1 variant (c.
Background: Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders.
View Article and Find Full Text PDFThe vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.
View Article and Find Full Text PDFObjective: Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia.
Methods: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation.
An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology.
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