致病性 DYT-THAP1 肌张力障碍突变导致少突胶质细胞发育不良和 YY1 结合缺失。
A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding.
机构信息
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
出版信息
Hum Mol Genet. 2022 Mar 31;31(7):1096-1104. doi: 10.1093/hmg/ddab310.
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.
肌张力障碍是一种致残性疾病，表现为长时间的不自主扭曲运动。DYT-THAP1 是一种由 THAP1 基因突变引起的孤立性肌张力障碍的遗传性形式，该基因编码转录因子 THAP1。phe81leu（F81L）错义突变代表了一类尚未被充分理解的突变，这些突变不会发生在对 DNA 结合至关重要的残基上。在这里，我们证明 F81L 突变（THAP1F81L）会损害 THAP1 的转录活性并破坏中枢神经系统髓鞘形成。引人注目的是，THAP1F81L 表现出正常的 DNA 结合，但导致其转录伙伴 YY1 的 DNA 结合显著减少，YY1 也在少突胶质细胞谱系进展中具有既定作用。我们的研究结果表明了一种分子发病机制模型，即 THAP1F81L 通常能结合 DNA，但不能有效地组织一个活跃的转录复合物。
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