Unveiling ZNF124 as a novel determinant in neurodegeneration: orchestration of photoreceptor homeostasis through MSX2 transcriptional regulation

Retinitis pigmentosa (RP), affecting more than 20 million people worldwide, refers to a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration and vision loss. However, the underlying genetic causes of substantial RP cases remain unidentified. In this report, we identified a novel homozygous splicing variant, c.219-1delG, which introduced skipping of exon 4 of the ZNF124 gene in a large RP pedigree by whole-exome sequencing analysis. To elucidate the pathogenesis of the mutation, we generated a retina-specific knockout mouse model of ZNF124 murine homologous gene Gm20541, which manifested RP-like phenotypes characterized by reduced electroretinogram response and progressive retinal degeneration. Integrated analysis using CUT&Tag, ChIP-exo, and RNA-seq data further revealed that ZNF124 regulated MSX2 expression through binding its promoter region. Moreover, deletion of Msx2in the retina led to thinning of retina owing to progressive degeneration of rod cells. Integrated analysis of RNA-seq data from both Gm20541 and Msx2 mutant retinas indicated that ZNF124 is essential for maintaining normal retinal function by regulating Msx2 transcription, which in turn controls the expression of murine homologues of retinal dystrophy genes Rs1, Pde6g, and Pdc. Taken together, our study identified a novel mechanism of transcriptional regulation for retinal homeostasis via ZNF124-MSX2 axis and ZNF124 as a novel candidate gene for RP.