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.
Dystonias with known genes include DYT1 and DYT6dystonia, presenting as isolated torsion dystonia, as well as DYT5 (dopa-responsive dystonia), DYT11 (myoclonus-dystonia), and DYT12 (rapid-onset dystonia-parkinsonism), where dystonia occurs in conjunction with other types of movement disorders.
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.
To further evaluate the mutational spectrum of THAP1 and its associated phenotype, we sequenced THAP1 in 567 patients with focal (n = 461), segmental (n = 68), or generalized dystonia (n = 38).
Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians.
Thanatos-associated protein domain containing, apoptosis-associated protein 1 (THAP1), the gene mutated in DYT6dystonia, encodes a transcription factor.