Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene

Abstract

Introduction: Leptin deficiency caused by mutations within the leptin gene (LEP) results in severe early onset obesity, hypogonadism, pubertal delay and immune system abnormalities. Constitutional delay in growth and puberty (CDGP) is a common condition seen in paediatric clinics, in which children present with delayed growth and puberty but usually also have a slim body habitus. We hypothesized that LEP variants may play a role in the phenotype seen in CDGP. Aim: To screen a group of children with CDGP for pathogenic sequence variants in LEP. Patients and methods: Denaturing HPLC was used to screen for LEP sequence variants in DNA samples from 78 children with CDGP (predominantly white males) and 112 control subjects. DNA fragments with a WAVE pattern deviant from wild type were directly sequenced. A STAT3 luciferase reporter assay in human embryonic kidney (HEK293) cells transiently transfected with the leptin receptor was used to test activity of mutant leptin. Results: One child with CDGP was identified to be heterozygous for a novel missense variant (c.68COG), which results in a proline to arginine substitution (p.P23R). This sequence variant was not identified in any of the other control subjects, but was identified in his mother who shared a similar phenotype of slim body habitus, reduced appetite and pubertal delay (menarche aged 15 years). The leptin variant showed similar stability in serum compared with wild type and did not demonstrate increased activity in an in vitro reporter gene assay. Conclusions: This is the first report of a sequence variant within the LEP gene associated with reduced body mass index rather than obesity. We hypothesize that this variant has increased bioactivity in vivo.

Leptin action in pubertal development: recent advances and unanswered questions

“…This indicates that the role of leptin in the onset of puberty depends on the individual development, strengthening the role of leptin as a permissive rather than definitive trigger of puberty. In a recent report, a novel missense variant in the leptin gene was identified in one individual from a cohort of children (78 subjects) with constitutional delay in growth and puberty (CDGP) (50). The sequence variant was not detected in control subjects (112 individuals), but was identified in his mother that also exhibited a lean constitution and delayed pubertal maturation.…”

Evaluation of fasting lipid profile and glycated hemoglobin in obese subjects at university of calabar teaching hospital, Nigeria

“…Combination of energy restriction, exercise, behavioral modifications, drugs and occasionally surgery should help in the management of obesity-related problems [10] however, for any significant progress to be made in the prevention of obesity, a public health approach is urgently needed [11].…”

Single-Nucleotide Polymorphisms in the LEPR Gene Are Associated with Divergent Phenotypes for Age at Onset of Puberty in Davisdale Ewes1

“…However, this mutation was not associated with central precocious puberty in girls [24], consistent with disruption of the leptin pathway potentially being detrimental to attainment of puberty, as was observed in the present study. Mutations in LEP resulting in leptin deficiency have also been associated with failure to undergo puberty and with obesity [25], and a rare mutation in LEP hypothesized to increase its bioactivity was associated with a thin body type and delayed puberty [26]. In Merino sheep, higher leptin concentrations were associated with earlier age at first estrus [8].…”