Genetic and functional analysis of ZMIZ1 in neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA): insights from muscle cells and signaling pathways

作者：Shan Li, Dafei Zhou, Yuyang Han, Chao Feng, Xiao‐Ming Lv, Gang Fu, Xing Wei, Chengai Wu, C. Yung Yu, Zheng Yang · 发表于：Pediatric Research · 年份：2025 · DOI：10.1038/s41390-025-04612-x · 被引用次数：2 · 研究领域：Connective tissue disorders research、Hereditary Neurological Disorders、Muscle Physiology and Disorders

BACKGROUND: Mutations in the ZMIZ1 gene have been implicated in neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA). However, the underlying cellular and physiological mechanisms remain poorly understood. METHODS: Exome sequencing was performed to identify candidate variants. qPCR, Western blot, immunofluorescence, CCK-8, and wound-healing assays were employed to assess gene function in human skeletal muscle cells (HSkMCs). RNA-seq and co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) were used for transcriptomic and interactome profiling. RESULTS: Here, we identified a novel de novo missense variant c.910G>C (p.A304P) in ZMIZ1 in a patient with NEDDFSA. The p.A304P variant significantly increased ZMIZ1 mRNA and protein expression levels and altered its subcellular localization. Functional assays demonstrated enhanced proliferation and migration in HSkMCs expressing the mutant ZMIZ1. qPCR validation revealed significant dysregulation of key genes in the TGF-β1 signaling pathway. Transcriptome analysis identified the cytokine-cytokine receptor interaction pathway as the most significantly enriched pathway. Additionally, we identified a novel interaction between ZMIZ1 and the transcription factor GTF2I. CONCLUSION: Our study identifies a novel likely pathogenic variant in ZMIZ1 associated with NEDDFSA. These findings provide new insights into the cellular and physiological mechanisms underlying NEDDFSA, highlighting ZMIZ1's ...