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<i>Background and Objectives:</i> Diabetes is a global health issue, with approximately 50% of patients developing diabetic nephropathy (DN) and 25% experiencing early and severe forms of the disease. The genetic factors contributing to rapid disease progression in a subset of these patients are unclear. This study investigates genetic variations in the <i>GLO-1</i>, <i>CBR-1</i>, and <i>ACE</i> genes associated with early and severe DN. <i>Materials and Methods:</i> Sanger DNA sequencing of the exons of <i>CBR1</i>, <i>GLO1</i>, and <i>ACE</i> genes was conducted in 113 patients with early and severe DN (defined as occurring within 10 years of the diagnosis of diabetes and with eGFR < 45 mL/min/1.73 m²) and 100 controls. The impact of identified genetic variations was analyzed using computational protein models created in silico with SWISS-Model and SWISS-Dock for ligand binding interactions. <i>Results:</i> In <i>GLO1</i>, two heterozygous missense mutations, c.102G>T and c.147C>G, and one heterozygous nonsense mutation, c.148G>T, were identified in patients. The SNP rs1049346 (G>A) at location 6:38703061 (GRCh38) was clinically significant. The c.147C>G mutation (C19S) was associated with ligand binding disruption in the GLO1 protein, while the nonsense mutation resulted in a truncated, non-functional protein. In <i>CBR1</i>, two heterozygous variations, one missense c.358G>A, and one silent mutation c.311G>C were observed, with the former (D120N) affecting the active site. No significant changes were noted in <i>ACE</i> gene variants concerning protein structure or function. <i>Conclusions:</i> The study identifies four novel and five recurrent mutations/polymorphisms in <i>GLO1</i>, <i>ACE</i>, and <i>CBR1</i> genes associated with severe DN in Pakistani patients. Notably, a nonsense mutation in <i>GLO1</i> led to a truncated, non-functional protein, while missense mutations in <i>GLO1</i> and <i>CBR1</i> potentially disrupt enzyme function, possibly accelerating DN progression.