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A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene.

ABSTRACT: Leptin (LEP) and leptin receptor (LEPR) play a major role in energy homeostasis, metabolism, and reproductive function. While effects of biallelic likely pathogenic variants (-/-) on the phenotype are well characterized, effects of mono-allelic likely pathogenic variants (wt/-) in the LEP and LEPR gene on the phenotype compared to wild-type homozygosity (wt/wt) have not been systematically investigated. We identified in our systematic review 44 animal studies (15 on Lep, 29 on Lepr) and 39 studies in humans reporting on 130 mono-allelic likely pathogenic variant carriers with 20 distinct LEP variants and 108 heterozygous mono-allelic likely pathogenic variant carriers with 35 distinct LEPR variants. We found indications for a higher weight status in carriers of mono-allelic likely pathogenic variant in the leptin and in the leptin receptor gene compared to wt/wt, in both animal and human studies. In addition, animal studies showed higher body fat percentage in Lep and Lepr wt/- vs wt/wt. Animal studies provided indications for lower leptin levels in Lep wt/- vs. wt/wt and indications for higher leptin levels in Lepr wt/- vs wt/wt. Data on leptin levels in human studies was limited. Evidence for an impaired metabolism in mono-allelic likely pathogenic variants of the leptin and in leptin receptor gene was not conclusive (animal and human studies). Mono-allelic likely pathogenic variants in the leptin and in leptin receptor gene have phenotypic effects disposing to increased body weight and fat accumulation.

SUBMITTER: Koerber-Rosso I

PROVIDER: S-EPMC8390564 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mechanical stress from haemodynamic perturbations or interventional manipulation of epicardial coronary atherosclerotic plaques with inflammatory destabilization can release particulate debris, thrombotic material and soluble substances into the coronary circulation. The physical material obstructs the coronary microcirculation, whereas the soluble substances induce endothelial dysfunction and facilitate vasoconstriction. Coronary microvascular obstruction and dysfunction result in patchy microinfarcts accompanied by an inflammatory reaction, both of which contribute to progressive myocardial contractile dysfunction. In clinical studies, the benefit of protection devices to retrieve atherothrombotic debris during percutaneous coronary interventions has been modest, and the treatment of microembolization has mostly relied on antiplatelet and vasodilator agents. The past 25 years have witnessed a relative proportional increase in non-ST-segment elevation myocardial infarction in the presentation of acute coronary syndromes. An associated increase in the incidence of plaque erosion rather than rupture has also been recognized as a key mechanism in the past decade. We propose that coronary microembolization is a decisive link between plaque erosion at the culprit lesion and the manifestation of non-ST-segment elevation myocardial infarction. In this Review, we characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for prevention and treatment. In this Review, Kleinbongard and Heusch characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for the prevention and treatment of this phenomenon. Key points Coronary microembolization results from spontaneous or interventional erosion or rupture of an epicardial coronary atherosclerotic plaque. Atherothrombotic plaque debris causes physical obstruction of coronary microvessels and results in microinfarcts with an inflammatory response. The surviving myocardium around the patchy microinfarcts has reduced contractile function as a result of inflammatory signal transduction leading to myofibrillar oxidation. Atherosclerotic plaque erosion or rupture releases soluble substances that induce coronary microvascular endothelial dysfunction, vasoconstriction, platelet aggregation and coagulation. Routine use of interventional protection devices does not improve patient outcomes but these devices are indicated in cases of high atherothrombotic plaque burden. Plaque stabilization with statins and canakinumab prevents coronary microembolization, whereas platelet inhibitors, vasodilators and interleukin antagonists attenuate coronary microvascular impairment.

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A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene.

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