Congenital Leptin Deficiency and Leptin Gene Missense Mutation Found in Two Colombian Sisters with Severe Obesity

Abstract

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

Obesity: Epidemiology, Pathophysiology, and Therapeutics

“…Leptin deficiency can cause diet-induced obesity and metabolic dysregulation. About 50% of female with polymorphism came up with binge eating ( 56 ). The MC4R polymorphism influences the release of ghrelin ( 57 ).…”

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin

“…The younger sister was 21 years old, with primary amenorrhea in addition to hypertriglyceridemia, insulin resistance, and acanthosis nigricans . Both patients exhibited breasts and genitals at Tanner Stage V, and undetectable leptin serum levels ( 81 ).…”

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

“…To date, many other mutations have been reported in the LEP gene in consanguineous families [ 99 , 100 , 101 , 102 ]. For example, Yupanqui-Lozno et al recently reported a novel homozygous missense mutation in LEP associated with very low serum leptin concentrations, hyperphagia and early-onset obesity in two severely obese sisters from Colombia born from consanguineous parents [ 103 ]. The analysis of serum leptin level is a useful test in patients with severe early-onset obesity, but it is also plausible that mutations in the LEP gene could result in a bioinactive form of the hormone in the presence of apparently appropriate leptin levels.…”