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.

Keywords: Animal; Humans; LEP; LEPR; Phenotype.

Fig. 1

Flowchart of the included studies reporting phenotype in animals as well as in humans with mono-allelic likely pathogenic variant A in the LEP and B in the LEPR gene

Fig. 2

A, B Illustration of individual BMI z scores in A children and B adults depending on LEP genotype (wt/wt vs. wt/- vs. -/-). A Children: LEP wt/wt (n = 2): mean: 0.5 (range 0.4–0.6); LEP wt/- (n = 8): mean − 0.1 (range − 2.4–1.3); LEP-/- (n = 25): mean 5.5 (range 2.7 − 12.5); B Adults: LEP wt/wt (n = 4): mean 0.3 (range − 1.0–1.0); LEP wt/- (n = 64): mean 1.0 (range − 0.9–4.2); LEP-/- (n = 13): mean 4.8 (range 4.1–5.2); C BMI z scores in association with LEP variant (green circle: wt/wt subject; blue square: wt/- subject; red triangle: -/- subject; yellow line: BMI z score = 1) (subjects reported in different studies, but showing the same variant are grouped together. It is not distinguished between children and adults. Only variants reported to be carried by wt/- are shown. However, not always a BMI z score for the wt/- carrier could be calculated; *p < 0.05)

Fig. 3

Illustration of individual body fat (BF) values [%] for children and adults in association with genotype for LEP (A, B) or LEPR (C, D) (wt/wt vs. wt/- vs. -/-; *p < 0.05). A Children: LEP wt/wt (n = 3): mean 17% (range 14–20%); LEP wt/- (n = 2): mean 19% (range 15–23%); LEP-/- (n = 6): mean 53% (range 50–57%). B Adults: LEP wt/wt (n = 0) LEP wt/- (n = 11): mean 28% (range 15–36%); LEP-/- (n = 2): mean 50.4% (range 42.8–57.9%); C Children: LEPR wt/wt (n = 7) mean 31% (range 18–49%); LEPR wt/- (n = 2): mean 20.5% (range 20–21%); LEPR-/- (n = 13): mean 54% (range 41–68%); D Adults: LEPR wt/wt (n = 7) mean 38% (range 20–52%); LEPR wt/- (n = 22) mean: 35% (range 18–48%); LEPR-/- (n = 7): mean 57% (range 50.7–66%)

Fig. 4

Leptin levels [ng/ml] in relation to BMI z score in LEP (A) and LEPR (B) variant carriers and wildtype subjects (wt/wt vs. wt/- vs. -/-). Data are shown for children and adults

Fig. 5

A, B Illustration of individual BMI z scores in children (A) and adults (B) depending on LEPR genotype (wt/wt vs. wt/- vs. wt/-; *p ≤ 0.05). A Children: LEPR wt/wt (n = 13): mean 0.5 (range 0.4–0.6); LEPR wt/- (n = 7): mean 0.9 (range − 1.6–2.4); LEPR-/- (n = 17): mean 5.7 (range 3.3–10.6); B Adults: LEPR wt/wt (n = 10): mean 2.5 (range 0.4–5.0); LEPR wt/- (n = 60): mean 1.2 (range − 1.0–3.8); LEPR-/- (n = 30): mean 4.5 (range 0.4–6.1); C BMI z scores in association with LEPR variant (green circle: wt/wt subject; blue square: wt/- subject; red triangle: -/- subject; unfilled red triangle: compound wt/- subject) (Only variants reported to be carried by wt/- are shown). However, not always a BMI z score for the wt/- carrier could be calculated. It is not distinguished between children and adults. Subjects reported in different studies, but showing the same variant are grouped together. If wt/wt subjects in one family with two different wt/- variants were described, they BMI z scores were plotted for both variants)