肌强直性营养不良1型模型小鼠的自闭症相关性状是由于自闭症风险基因的MBNL隔离和RNA错剪接，这一成果由佛罗里达大学Ryan K. C. Yuen研究小组经过不懈努力而取得。2025年4月21日出版的《自然—神经科学》杂志发表了这一最新研究成果。

该课题组报道了MBNL剪接因子被扩增CUG重复序列的突变DMPK RNA隔离，改变了大脑发育过程中自闭症风险基因的RNA剪接模式，特别是一类自闭症相关的微外显子。课题组证明DMPK-CTG扩展和MBNL零主题模型都概括了自闭症相关的错误剪接特征，以及社会行为缺陷和对新奇事物的改变反应。这些发现支持了他们的模型，即肌强直性营养不良相关的自闭症是由自闭症风险基因的发育错误剪接引起的。

据了解，基因特异性串联重复扩增的全基因组富集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CTG串联重复扩增，已知该突变可导致1型肌强直性细胞营养不良。虽然自闭症和肌强直性营养不良之间有明确的临床联系，但这种联系的分子基础仍不清楚。

附：英文原文

Title: Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes

Author: Sznajder, ukasz J., Khan, Mahreen, Ciesioka, 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.

Issue&Volume: 2025-04-21

Abstract: 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.

DOI: 10.1038/s41593-025-01943-0

Source: https://www.nature.com/articles/s41593-025-01943-0