A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding.
Hum Mol Genet
; 31(7): 1096-1104, 2022 03 31.
Article
em En
| MEDLINE
| ID: mdl-34686877
ABSTRACT
Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Distúrbios Distônicos
/
Distonia
/
Distonia Muscular Deformante
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article