LEPR – Obesity due to Leptin Receptor Gene Deficiency

Leptin receptor (LEPR) deficiency is an autosomal recessive disorder characterized by early-onset severe obesity, hyperphagia, and variable pituitary hormone deficiencies. A systematic review identified 88 published patients worldwide (21 European) with biallelic LEPR variants, yielding an estimated European prevalence of 1.34 per 1 million (PMID:31658438). Clinical features include extreme hunger, rapid weight gain in infancy, and, in many, hypogonadotropic hypogonadism and metabolic dysregulation.

Genetic evidence supports autosomal recessive inheritance with homozygous or compound heterozygous variants segregating with disease. Over 38 distinct LEPR mutations—including missense, nonsense, splice, and frameshift alleles—have been reported across multiple consanguineous and non-consanguineous families. For example, c.2168C>T (p.Ser723Phe) was identified in a 10.5-year-old girl with hyperphagia and class III obesity (PMID:37393902).

Segregation data from large case series demonstrate co-segregation of biallelic LEPR variants with obesity and endocrine features in affected sibships. Consistent molecular findings across unrelated families confirm the autosomal recessive pattern and high penetrance of biallelic loss-of-function alleles (PMID:30560226).

Functional studies reveal that pathogenic LEPR variants impair receptor trafficking and leptin-mediated STAT3 activation. Cell-based assays show reduced cell-surface expression and blunted signaling for multiple variants, including p.Ser723Phe and p.Leu662Ser (PMID:33221380). In vitro read-through experiments further characterize nonsense alleles, guiding potential therapeutic strategies for translational suppression.

Animal models corroborate human findings: the Zucker fatty rat Gln269Pro mutation causes intracellular retention and signaling incompetence of LEPR (PMID:9660803). Moreover, LEPR-null mice expressing a neuronally driven LEPR-B transgene partially restore energy homeostasis, fertility, and neuropeptide expression, underscoring the critical role of LEPR-B in hypothalamic regulation (PMID:11272157).

The advent of targeted pharmacotherapies, such as MC4R agonists, has shown efficacy in resolving hyperphagia and reducing BMI in LEPR-deficient patients, highlighting the importance of genetic diagnosis for personalized treatment (PMID:37393902).

Collectively, the genetic and functional concordance across human cases and animal models establishes a strong gene–disease link. Clinical testing for LEPR variants in early-onset obesity is evidence-based, enabling precise diagnosis and informed therapeutic decisions.

Key take-home: Identification of biallelic LEPR mutations in patients with severe early-onset obesity is clinically actionable, guiding targeted pharmacotherapy and family counseling.

References

• Obesity facts • 2023 • The Narrative of a Patient with Leptin Receptor Deficiency: Personalized Medicine for a Rare Genetic Obesity Disorder. PMID:37393902
• European journal of endocrinology • 2020 • Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics. PMID:31658438
• Journal of the Endocrine Society • 2019 • Functional and Phenotypic Characteristics of Human Leptin Receptor Mutations. PMID:30560226
• Metabolism: clinical and experimental • 2021 • Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity. PMID:33221380
• The Journal of biological chemistry • 1998 • Altered cell surface expression and signaling of leptin receptors containing the fatty mutation. PMID:9660803
• Diabetes • 2001 • Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. PMID:11272157

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