RESUMEN
Background: Previously, numerous case-control studies have highlighted variants responsible for Maturity onset diabetes of young (MODY). However, these studies have been conducted among diverse populations and hence yielded contradictory results. We, therefore, performed a meta-analysis to precisely find the association of SNPs with the disease for the HNF1A gene. Objective: Meta-analysis of clinically defined studies deciphering mutations in the HNF1A gene responsible for the development of MODY3 was conducted among various populations to determine associations using statistical approaches. Methods: The curation of 505 research articles published between the years 2000-2021 was carried out. Visualization of data-related protocols and statistical-analysis were conducted, which led to the identification of highly prevalent mutations among different populations (majorly Europe). Further comparison between the frequencies of the control (healthy population) and test (diseased population) dataset generated through curation was performed. Results: We identified nine MODY3 mutations (rs587776825, rs1169288, rs1800574, rs2464196, rs137853244, rs137853238, rs587780357, rs137853240 and rs137853243) at the genome-wide significance level ( p < 5.0 × 10-8). The present study confirmed that the data does not follow a normal distribution. Further, the data was confirmed to be a more homogenous type with frequencies having a significant association with the disease. Conclusion: This meta-analysis found significant associations of mutations in HNF1A with MODY3, consistent with previous studies. Our findings should help elucidate the mutations in a compiled form responsible for causing MODY3. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-00975-8.
RESUMEN
Constitutively active K-Ras oncogene mutation at G12V changes the proteome of cells and activates macroautophagy for cell advantage. Inhibition of macroautophagy impairs K-Ras mediated tumor progression to a limited extent with increase of spontaneous tumors due to poorly understood mechanisms. Here, we show that inhibition of macroautophagy in K-Ras G12V mouse embryonic fibroblasts (MEFs) hyper activates chaperon mediated autophagy (CMA). Quantitative identification of CMA substrates through co-immunoprecipitation of CMA component heat shock cognate 70 (Hsc70) demonstrates a shift of proteins from macroautophagy to CMA mediated degradation. However, macroautophagy impairment show significant inhibition on proliferation and CMA hyper activation provides a basal support to macroautophagy-inhibited MEFs for survival. On the other hand, K-Ras G12V MEFs impaired of CMA reduces number of Hsc70 clients but activated macroautophagy significantly compensated CMA loss. Nonetheless, co-inhibition of CMA and macroautophagy had a synergistic detrimental effect on both proliferation and survival of MEFs expressing K-Ras G12V mutant. Our results point to K-Ras G12V MEFs dependency on macroautophagy and CMA partly compensates its loss for survival but not hyper-proliferation; implicating that targeting both macroautophagy and CMA as a promising therapeutic target in G12V mutation associated K-Ras cancers. SIGNIFICANCE: The present study provides a framework of Hsc70 interacting proteins, which differentially interact with Hsc70 in response to autophagy alterations. The role of proteins accumulation and induced proteo-toxicity could be underlying factor in macroautophagy and CMA co-inhibited K-Ras G12V MEFs phenotype. Our study provides rational for adaptive mechanisms in K-Ras tumors inhibited with different autophagy pathways and also supports targeting both macroautophagy and CMA simultaneously as therapeutic target. At the same time current study will help in characterizing the underlying cellular processes that may play a role in escaping tutor suppressor role CMA and macroautophagy in cancers harboring K-Ras G12V mutation that may be further utilized to identify molecular targets for K-Ras-driven cancers.