Functional characterization of the short-dehydrogenase reductase protein SDR42E1

Vitamin D (VD) deficiency is a globally prevalent nutritional deficiency, with 25-hydroxyVD (25(OH)D) concentrations below 20 ng/mL. Recent genome-wide association studies have identified a nonsense SNP in the novel, uncharacterized short-chain dehydrogenase/reductase gene SDR42E1, which is believed to play a crucial role in regulating steroid synthesis. Our objective is to characterize the functions and expressions of SDR42E1 through bioinformatic analyses and a multi-omics approach. Our published virtual screening revealed strong binding affinities between SDR42E1 and its nematode orthologs with VD precursors and metabolites, facilitated by the NADP+ cofactor that stabilizes steroid substrate binding. We will employ CRISPR/Cas9 gene-editing technology to completely knockout SDR42E1 in HaCat and HCT116 lines, validating these findings in primary keratinocytes and intestinal epithelial cells, and subsequently in C. elegans. We will investigate SDR42E1’s metabolic roles using flow cytometry, apoptosis assays, and VD quantification via ELISA. Further, we will employ an integrated multi-omics approach—combining transcriptomics and LC-MS/MS-based proteomics and lipidomic profiling—to examine the downstream effects of SDR42E1. This comprehensive approach aims to illuminate the critical role of SDR42E1 and its implications for precision medicine in managing VD deficiency.

Hamad Bin Khalifa University (HBKU)