Sznajder Łukasz J, Khan Mahreen, Ciesiołka Adam, Tadross Mariam, Nutter Curtis A, Taylor Katarzyna, Pearson Christopher E, Lewis Mark H, Hines Rochelle M, Swanson Maurice S, Sobczak Krzysztof, Yuen Ryan K C
Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV, USA.
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL, USA.
Nat Neurosci. 2025 Apr 21. doi: 10.1038/s41593-025-01943-0.
Genome-wide enrichment of gene-specific tandem repeat expansions has been linked to autism spectrum disorder. One such mutation is the CTG tandem repeat expansion in the 3' untranslated region of the DMPK gene, which is known to cause myotonic muscular dystrophy type 1. Although there is a clear clinical association between autism and myotonic dystrophy, the molecular basis for this connection remains unknown. Here, we report that sequestration of MBNL splicing factors by mutant DMPK RNAs with expanded CUG repeats alters the RNA splicing patterns of autism-risk genes during brain development, particularly a class of autism-relevant microexons. We demonstrate that both DMPK-CTG expansion and Mbnl null mouse models recapitulate autism-relevant mis-splicing profiles, along with social behavioral deficits and altered responses to novelty. These findings support our model that myotonic dystrophy-associated autism arises from developmental mis-splicing of autism-risk genes.
全基因组范围内基因特异性串联重复序列扩增与自闭症谱系障碍有关。其中一种突变是DMPK基因3'非翻译区的CTG串联重复序列扩增，已知该突变会导致1型强直性肌营养不良。尽管自闭症与强直性肌营养不良之间存在明确的临床关联，但这种联系的分子基础仍然未知。在这里，我们报告，具有扩展CUG重复序列的突变DMPK RNA对MBNL剪接因子的隔离会改变大脑发育过程中自闭症风险基因的RNA剪接模式，特别是一类与自闭症相关的微小外显子。我们证明，DMPK-CTG扩增和Mbnl基因敲除小鼠模型都重现了与自闭症相关的错误剪接谱，以及社交行为缺陷和对新奇事物反应的改变。这些发现支持了我们的模型，即强直性肌营养不良相关的自闭症源于自闭症风险基因的发育性错误剪接。
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