THAP1 – torsion dystonia 6

THAP1 mutations cause DYT6 primary dystonia, an autosomal dominant movement disorder with incomplete penetrance. The first linkage of THAP1 (HGNC:20856) to torsion dystonia 6 (MONDO:0011264) demonstrated nine coding variants in 362 genetically undetermined British dystonia patients, including the founder c.7C>T (p.Gln3Ter) change in the THAP domain (PMID:20211909). Amish-Mennonite and European families contributed the initial cohort of 13 mutations, establishing THAP1 as a causative gene for early-onset craniocervical dystonia. Penetrance is estimated at ~30%, consistent with autosomal dominant inheritance and variable expressivity.

Subsequent studies expanded the mutational spectrum: two additional heterozygous mutations were found in 228 focal and segmental cases (PMID:22903657), and six novel pathogenic variants—including missense and frameshift changes—were identified among 567 dystonia patients, defining a mutation frequency of 1.1% (PMID:21847143). The spectrum comprises missense (e.g., p.Arg169Gln), nonsense (e.g., p.Arg29Ter), frameshift (e.g., Asp191ThrfsTer9), and splice or promoter alterations (c.71+9C>A), with concentration in the THAP domain and coiled-coil regions. Recurrent alleles, such as c.77C>T (p.Pro26Leu), suggest mutational hotspots. A promoter variant, c.71+9C>A, alters splicing and increases adult-onset dystonia risk (PMID:24936516).

Familial segregation has been documented across multiple pedigrees: six additional affected relatives carrying THAP1 variants display focal or segmental dystonia, confirming co-segregation with disease. Multi-population screening (German, Chinese, Polish cohorts) identified 2.5%–0.87% of cases harboring heterozygous THAP1 mutations, often with laryngeal or oromandibular involvement (PMID:19345148; PMID:21839475). In three German families, eight mutation carriers (three symptomatic, three subtle carriers) showed early-onset spasmodic dysphonia and increased substantia nigra echogenicity on transcranial ultrasound (PMID:20687193).

Clinically, DYT6 presents before age 30 with primary craniocervical or limb dystonia, often progressing to segmental or generalized forms. Focal dystonia (HP:0004373), generalized dystonia (HP:0007325), laryngeal dystonia (HP:0012049), and torticollis (HP:0000473) are common. Speech involvement occurs in >40% of cases, and writer’s cramp or limb-onset dystonia can precede generalized spread. Phenotypic variability underscores the importance of THAP1 screening in early-onset, nonfocal dystonia.

Functional studies support a haploinsufficiency mechanism via transcriptional dysregulation. Biophysical assays revealed that THAP domain mutations (e.g., p.Arg29Pro, p.Pro26Leu) reduce protein stability and alter DNA-binding specificity (PMID:22844099). THAP1 autoregulates its promoter via HCFC1 recruitment; pathogenic mutants (Ser6Phe, Arg13His) disrupt this feedback, increasing THAP1 expression in neurons (PMID:25088175). Mouse models bearing the C54Y knock-in exhibit motor deficits, cerebellar-nuclear alterations, and transcriptional changes overlapping other dystonia pathways (PMID:26376866).

No studies have refuted THAP1’s role in DYT6, and functional assays consistently show concordant molecular defects. The cumulative evidence—over 30 unrelated probands, multi-family segregation, varied variant classes, and reproducible functional data—supports a definitive gene-disease relationship. Key take-home: THAP1 genetic testing is critical for diagnosis, prognostic counseling, and targeted research in early-onset cranio-cervical dystonia.

References

• Neurology • 2010 • THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. PMID:20211909
• Movement disorders • 2012 • THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. PMID:22903657
• European journal of human genetics • 2012 • Identification and functional analysis of novel THAP1 mutations. PMID:21847143
• The Lancet. Neurology • 2009 • Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. PMID:19345148
• Nucleic acids research • 2012 • Towards the classification of DYT6 dystonia mutants in the DNA-binding domain of THAP1. PMID:22844099
• Biochimica et biophysica acta • 2014 • THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression. PMID:25088175
• Human molecular genetics • 2015 • Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia. PMID:26376866

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