Our goal was to characterize patients with inherited and isolated dystonia and determine the frequency of mutations responsible for DYT1 and DYT6 in Brazilian patients.
Our findings strongly suggest the role of other genetic factors or environmental triggers in the pathogenesis of dystonia related to mutations in THAP1 gene.
Carriers were less likely to have dystonia restricted to a single site (11.11% in carriers vs. 65.9% in noncarriers; P < 0.01) and were less likely to have dystonia onset in cervical regions (25.9% of THAP1 carriers vs. 52.5% of noncarriers; P = 0.04).
After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia.
We analyzed 610 patients with various forms of dystonia for sequence variants in the THAP1 gene by means of high resolution melting to delineate the prevalence of sequence variants and phenotypic variability.
Mutations in the thanatos-associated protein domain containing apoptosis-associated protein 1 gene (THAP1) are responsible for adult-onset isolated dystonia (DYT6).
Patients presenting with early-onset cervical dystonia should be screened for THAP1 gene mutations to fully assess all the possible etiologies of dystonia.
We identified a de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patient with early onset generalized dystonia with speech involvement.
Thanatos-associated protein domain containing, apoptosis-associated protein 1 (THAP1), the gene mutated in DYT6dystonia, encodes a transcription factor.
Here, I review the clinical genetics and cell biology of three forms of inherited dystonia for which the causative mutation is known: DYT1 (TOR1A), DYT6 (THAP1), DYT25 (GNAL).
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).
A total of three nucleotide variants were detected, which include a reported missense mutation (c.427 A>G; p.Met143Val) in a juvenile onset generalized dystonia patient, a novel frameshift deletion mutation (c.208-209 ΔAA; p.K70VfsX15) in a juvenile onset cervical dystonia patient and a rare variant in 3' UTR of THAP1 (c.*157 T>C) in an adult-onset blepharospasm patient.
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.