Association of MT-ATP6 gene mutations with the pathogenesis of chronic kidney disease in human

Abstract

BackgroundChronic kidney disease (CKD) is one of the major global health problems. CKD patients are at increased risk of cardiovascular diseases, anemia, mineral, and bone disorders, decreased quality of life, and early death. Involvement of mitochondria is increasingly recognized in genetic and acquired CKD. Mitochondrial dysfunctions are caused by many pathogenic mutations localized in the mitochondrial gene (MT-ATP6) that encodes the subunit ‘a’ of ATP synthase. ObjectivesThe aim of this study was to identify the MT-ATP6 gene mutations in patients with CKD and assess the relationship between MT-ATP6 gene mutation with CKD. Materials and methodsIn this study, blood samples of 18 CKD patients and 21 healthy controls were analyzed. Genomic DNA was extracted from the collected blood samples; the MT-ATP6 region was amplified by polymerase chain reaction (PCR); PCR products was purified; and direct sequencing was performed. In addition, sequencing data was further analyzed with various in silico tools. ResultsIn this study it was found that the serum creatinine concentration of CKD patients was approximately 7.5 folds higher than that of healthy controls. According to the criteria based on the estimated glomerular filtration rate (eGFR), it was determined that 78% of the patients were in stage-5 (eGFR <15 mL/min/1.73 m2) and the rest of the patients were in stage-4 (eGFR between 15 and 29 mL/min/1.73 m2) of CKD. Analyzing MT-ATP6 gene sequences of CKD patients, eight novel mutations (m.8732C>G, m.8800_8801insG, m.8804C>G, m.8947C>G, m.8983C>G, m.8999T>G, m.9059C>G, and m.9129C>G) along with 11 reported mutations were identified. In the case of CKD patients, 14 nonsynonymous mutations in the MT-ATP6 gene were detected and 8 of them were damaging and disease-causing based on in silico analyses with five different tools. On the other hand, only 3 nonsynonymous mutations were identified in healthy individuals, which were all neutral and tolerating mutations according to in silico analyses. In this study, a significant correlation between non-synonymous MT-ATP6 gene mutations and occurrence of CKD (p-value <0.0001) was also observed. ConclusionsThe results revealed that there is a link between MT-ATP6 gene mutation and the development of CKD. It can be concluded that mutations in the MT-ATP6 gene may have a role in CKD development.