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Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients

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Abstract

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by the variants in MODY-related genes. In addition to coding variants, variants in the promoter region of MODY-related genes can cause the disease as well. In this study, we screened the promoter regions of the most common MODY-related genes GCK, HNF1A, HNF4A and HNF1B in our cohort of 29 MODY patients. We identified one genetic variant in the HNF1A gene, a 7 bp insertion c.-154-160insTGGGGGT, and three variants in the GCK gene, −282C>T; −194A>G; 402C>G appearing as set. Chloramphenicol acetyltransferase (CAT) assay was performed to test the effect of the 7 bp insertion and the variant set on the activity of the reporter gene in HepG2 and RIN-5F cell, respectively, where a decreasing trend was observed for both variants. In silico analysis and electrophoretic mobility shift assay showed that the 7 bp insertion did not create the binding site for new transcriptional factors, but gave rise to additional binding sites for the existing ones. Results from our study indicated that the 7 bp insertion in the HNF1A gene could be associated with the patient’s diabetes. As for the GCK variant set, it is probably not associated with diabetes in patients, but it may modify the fasting glucose level by causing small elevation in variant set carriers. We have presented two promoter variants in MODY-related genes. Variant in the HNF1A gene is presumed to be disease-causing and the GCK promoter variant set could be a phenotype modifier.

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Funding

This work was supported by Ministry of Education, Science and Technological Development Republic of Serbia, EB: 451-03-68/2020-14/200042.

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Authors and Affiliations

  1. Institute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Biomedicine, University of Belgrade, Belgrade, Serbia

    Jovana Komazec, Bojan Ristivojevic, Branka Zukic, Teodora Karan-Djurasevic, Sonja Pavlovic & Milena Ugrin

  2. University Children’s Hospital, University of Belgrade, Belgrade, Serbia

    Vera Zdravkovic

  3. School of Medicine, University of Belgrade, Belgrade, Serbia

    Vera Zdravkovic

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  1. Jovana Komazec
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  2. Bojan Ristivojevic
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  5. Teodora Karan-Djurasevic
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  6. Sonja Pavlovic
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Contributions

J.K. performed research and analyzed data; wrote the manuscript. M.U. designed the study and supervised the research; wrote the manuscript. B.R. and B.Z. performed research and analyzed data. V.Z. provided clinical data analysis. S.P. design and supervised the study, provided critical revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Milena Ugrin.

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The study was approved by the Ethics Committee of the University Children’s Hospital, Belgrade (Approval Number 017/6-26/77) and was performed in accordance with the ethical standards of the Declaration of Helsinki.

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Informed consent was obtained from all the participants that were old enough to give their own consent, and from the parents/legally authorized representatives of the minor subjects of the study.

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Komazec, J., Ristivojevic, B., Zukic, B. et al. Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients. Mol Biol Rep 47, 6759–6768 (2020). https://doi.org/10.1007/s11033-020-05734-7

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