Cross-tissue transcriptomic analysis identifies molecular signatures of GPR143 deficiency in ocular albinism type 1

Ocular albinism type 1 (OA1) is an X-linked disorder caused by pathogenic variants in GPR143 . Although ocular phenotypes and melanosome abnormalities are well described, the molecular pathogenesis—especially potential effects beyond the eye—remains incompletely understood. We aimed to identify the causative variant in a large pedigree with OA1 and to delineate transcriptomic changes associated with GPR143 deficiency across tissues. Whole-genome sequencing (WGS) was performed on a six-generation pedigree to screen for pathogenic variants. To investigate the molecular consequences of Gpr143 disruption, a CRISPR/Cas9-generated Gpr143 deletion-mutant (Gpr143 − 28/Y ) mouse model carrying a distinct 28-bp deletion was used. Phenotypic characterization was conducted, followed by comparative whole-transcriptome RNA sequencing (RNA-seq) on both brain and eye tissues from wild-type and mutant mice. Differential gene expression analysis and functional pathway enrichment (GO and KEGG) were utilized to identify molecular signatures. A novel 74-bp deletion in exon 1 of GPR143 (NM_000273.3:c.110_183del) was identified in five affected males and three female carriers from the OA1 pedigree. The Gpr143 − 28/Y mice recapitulated key OA1 phenotypes, exhibiting reduced ocular pigmentation and mildly reduced ocular globe size. Transcriptomic analysis revealed distinct molecular alterations: in the brain, Gpr143 deficiency led to the upregulation of genes involved in mitochondrial metabolism and the PPAR signaling pathway, alongside the downregulation of synaptic function-related genes. In the eye, pathways associated with ion channel activity and muscle contraction were activated, which may be relevant to ocular dysfunction in OA1. Integrated analysis identified 88 common differentially expressed genes (DEGs) across both tissues, which were significantly enriched in lipid metabolism and calcium signaling pathways. This study identifies a novel GPR143 deletion associated with OA1 and characterizes transcriptomic alterations in eye and brain tissues. Our findings reveal shared and tissue-specific transcriptional signatures associated with Gpr143 deletion, providing new insights into the molecular changes potentially associated with OA1 beyond ocular pigmentation.