RNA-binding proteins regulate immune-related alternative splicing in inherited salt-losing tubulopathies

Inherited salt-losing tubulopathies (SLT) are rare disorders caused by gene mutations that disrupt renal tubular ion transport. However, the molecular mechanisms underlying SLT pathogenesis remain unclear. This study aims to elucidate the functional genes and potential regulatory mechanisms associated with SLT.

We established a study cohort comprising inherited SLT patients, age-matched patients with acquired hypokalemia, and healthy volunteers. Clinical characteristics were compared among the groups. RNA sequencing (RNA-seq) was performed to obtain transcriptomic profiles, followed by analysis of gene expression patterns and alternative splicing events (ASEs). Key findings were validated using RT-qPCR.

SLT patients exhibited a higher prevalence of recurrent viral infections (65%, P = 0.004) and autoimmune thyroid disorders (30%, P = 0.022) compared to healthy controls. RNA-seq analysis identified 2,611 differentially expressed genes (DEGs) in SLT patients, including 1,236 upregulated and 1,375 downregulated genes. These DEGs were primarily enriched in innate immune responses and adaptive immunity pathways. Additionally, significant alterations in gene expression related to viral defense and stress responses were observed. Notably, we identified several RNA-binding proteins (RBPs) that may contribute to SLT pathogenesis by regulating ASEs of immune-related genes.

Our findings highlight the critical role of RBPs in SLT pathogenesis and provide novel insights into the immune profiles and gene expression dynamics in SLT. This study lays the foundation for future research into targeted therapies and personalized treatment strategies for SLT management.