期刊
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
卷 49, 期 1, 页码 -出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2021.5065
关键词
ADCY3; variants; obesity; body mass index; molecular modelling
资金
- AG Leventis Foundation [3317312]
- RCB Bank Ltd. [33173151]
Severe early-onset obesity is often caused by single gene variations of the hypothalamic leptin-melanocortin system, with ADCY3 being a key genetic candidate. A new pathogenic variant was discovered through genomic sequencing, highlighting the potential impact on protein structure and function. These findings suggest the involvement of ADCY3 in the disease.
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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