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.

Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

“…Generally, heterozygous variants were previously detected in unaffected individuals (5, 7). Heterozygous carries generally show lower BMI z-scores and lower body fat percentage than homozygous individuals (28). Yet, it is feasible that an additive effect of heterozygous variants may still have an impact on the carrier’s body weight.…”

“…The non-synonymous mutations p.Asp100Asn (rs724159998, 30), p.Asn103Lys (rs28954113, 6, 31, 32) and the frameshift mutation p.Gly133Val fs Ter15 (rs1307773933, 7) were detected in extremely obese children being homozygous carriers (5). Another study showed that BMI z-scores of carriers of homozygous LEP variants are generally higher than those of the heterozygous or wildtype individuals carrying the same variant (28).…”

Lower Circulating Leptin Levels Are Related to Non-Alcoholic Fatty Liver Disease in Children With Obesity

“…Furthermore, a systematic literature review provided evidence for a higher frequency of metabolic abnormalities in LEP wt/- than in wt/wt subjects, including hypercholesterinemia, hyperinsulinemia, and hypertriglyceridemia. Animal studies demonstrated lower leptin levels in LEP wt/- compared to wt/wt animals, especially in relation to fat mass ( 23 ). Furthermore, in humans with lipodystrophies, a group of disorders that are characterized by a selective deficiency of subcutaneous adipose tissue and low circulating leptin levels, severe forms of NAFLD have been described together with other metabolic complications including insulin resistance and high triglyceride levels.…”

Mechanism of receptor assembly via the pleiotropic adipokine Leptin

“…Several mutations in Leptin and LEP-R, including deletions, frameshifts and single nucleotide polymorphisms (SNPs), are associated with severe obesity and other diseases 12, 49 . Here we focus on pathogenic SNPs with no currently known effect on secretion levels and stability ( Extended Data Table 2, Extended Data Fig.…”