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.
Highlights
Obesity is a pandemic worldwide and is closely associated with multiple metabolic disturbances including diabetes, hyperlipidemia, nonalcoholic fatty liver disease, hypertension, and cardiovascular diseases, as well as various types of cancer
Our first report is a 24-year-old female, referred to as OBX1 (Figure 1A). She was first seen in the practice setting at age 9 for early childhood-onset morbid obesity, primary amenorrhea, and acne on the chest
There was no presence of failure to thrive during the first two years
Summary
Obesity is a pandemic worldwide and is closely associated with multiple metabolic disturbances including diabetes, hyperlipidemia, nonalcoholic fatty liver disease, hypertension, and cardiovascular diseases, as well as various types of cancer. Most forms of obesity [5] are influenced by both genetic [6] and environmental factors, monogenic obesity is a very rare type of obesity, which is caused by a mutation in a single gene and is usually not significantly affected by the environmental factors, resulting in severe obesity in early childhood [7]. Congenital leptin deficiency (CLD) is a rare human genetic disorder caused by homozygous mutations of the LEP gene resulting in severe hyperphagia and early-onset obesity [11]. 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. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS)
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