Open AccessA pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding
Author(s) -
Dhananjay Yellajoshyula,
Abigail Rogers,
Audrey J. Kim,
Sumin Kim,
Samuel S. Pappas,
William T. Dauer
Publication year - 2021
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddab310
Subject(s) - biology , missense mutation , genetics , mutation , transcription factor , dna , yy1 , transcription (linguistics) , dystonia , dna binding protein , gene , microbiology and biotechnology , gene expression , neuroscience , promoter , linguistics , philosophy
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.