Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

Toumba,Meropi; Fanis,Pavlos; Vlachakis,Dimitrios; Neocleous,Vassos; Phylactou,Leonidas A.; Skordis,Nicos; Mantzoros,Christos S.; Pantelidou,Maria

doi:10.3892/ijmm.2021.5065

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

Authors:
- Meropi Toumba
- Pavlos Fanis
- Dimitrios Vlachakis
- Vassos Neocleous
- Leonidas A. Phylactou
- Nicos Skordis
- Christos S. Mantzoros
- Maria Pantelidou
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Affiliations: Pediatric Endocrinology Clinic, Department of Paediatrics, Aretaeio Hospital, 2024 Nicosia, Cyprus, Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus, Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA, Department of Pharmacy, School of Health Sciences, Frederick University Cyprus, 1036 Nicosia, Cyprus
Published online on: November 24, 2021 https://doi.org/10.3892/ijmm.2021.5065
Article Number: 10
Copyright: © Toumba et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Severe early‑onset obesity is mainly attributed to single gene variations of the hypothalamic leptin‑melanocortin system, which is critical for controlling the balance between appetite and energy expenditure. Adenylate cyclase 3 (ADCY3), a transmembrane enzyme localized in primary neuronal cilia, is a key genetic candidate, which appears to have an essential role in regulating body weight. The present study aimed to identify ADCY3 genetic variants in severely obese young patients of Greek‑Cypriot origin by genomic sequencing. Apart from previously reported variants, the novel and probably pathogenic variant c.349T>A, causing a p.Leu117Met substitution within one of the two pseudo‑symmetric halves of the transmembrane part of the protein, was reported. Molecular modelling analysis used to delineate bonding interactions within the mutated protein structure strongly suggested a change in interactive forces and energy levels affecting the pseudo‑twofold symmetry of the transmembrane domain of the protein and probably its catalytic function. These results support the involvement of ADCY3 in the pathology of the disease and point towards the requirement of defining protein function and evaluating the clinical significance of the detected variants.

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