Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.
Open accessAbstract
BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.
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Subjects with mutations of the leptin gene or the leptin receptor gene present with normal adrenal function.
“In contrast to findings in rodents, subjects with mutations of the leptin gene or the leptin receptor gene present with normal adrenal function (16,18).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [16]
Subjects with congenital leptin deficiency or loss of leptin function because of leptin mutations or leptin receptor mutations have clinically evident hypogonadotropic hypogonadism and present with low concentrations of follicle-stimulating hormone and luteinizing hormone, complete loss of luteinizing hormone pulsatility, lack of pubertal growth spurt, reduced expression of secondary sexual traits
“Subjects with congenital leptin deficiency or loss of leptin function because of leptin mutations or leptin receptor mutations have clinically evident hypogonadotropic hypogonadism and present with low concentrations of follicle-stimulating hormone and luteinizing hormone and complete loss of luteinizing hormone pulsatility, lack of pubertal growth spurt, reduced expression of secondary sexual”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [16]
Single-gene Mendelian defects account for about 8% (or perhaps more) of cases of morbid human obesity.
“The importance of the aforementioned neural circuits for human obesity has been established in a series of genetic studies in which it has been shown that single-gene Mendelian defects account for '8% (or perhaps more) of cases of morbid human obesity (55)(56)(57)(58)(59)(60)(61)(62)(63).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [55]
Homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings.
“The finding that homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings emphasises the role of leptin in reproduction.98–100”
From Pubertal development and regulation (2016) · cites this paper as [98]
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- Authors
- Farooqi, I. S., Wangensteen, T., Collins, S., Kimber, W., Matarese, G., Keogh, J. M., Lank, E., Bottomley, B., Lopez-Fernandez, J., Ferraz-Amaro, I., Dattani, M. T., Ercan, O., Myhre, A. G., Retterstol, L., Stanhope, R., Edge, J. A., McKenzie, S., Lessan, N., Ghodsi, M., De Rosa, V., Perna, F., Fontana, S., Barroso, I., Undlien, D. E., & O'Rahilly, S.
- Affiliations
- University of Cambridge (GB)
- University of Oslo (NO)
- Wellcome Sanger Institute (GB)
- Addenbrooke's Hospital (GB)
- Institute for Experimental Endocrinology and Oncology (IT)
- Istanbul University-Cerrahpaşa (TR)
- Great Ormond Street Hospital (GB)
- John Radcliffe Hospital (GB)
- Royal London Hospital (GB)
- Shariati Hospital (IR)
- University of Naples Federico II (IT)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2007-01-18
- Volume
- 356
- Issue
- 3
- Pages
- 237-247
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2670197
- OpenAlex
- W1994545264
- Cited by
- 732
- References
- 32
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 26 · 2023: 39 · 2022: 26 · 2021: 46 · 2020: 31 · 2019: 37 · 2018: 35 · 2017: 46 · 2016: 32 · 2015: 43 · 2014: 47 · 2013: 43 · 2012: 48
- FWCI
- 19.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (077016, 068086, 067457)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin receptor deficiency, early-onset obesity, hyperphagia, consanguineous family, hypogonadotropic hypogonadism, delayed puberty, immune function, leptin levels, receptor signaling
- MeSH terms
- Adult, Basal Metabolism, Body Composition, Child, Diagnosis, Differential, Female, Genotype, Humans, Hyperphagia, Hypogonadism, Immunologic Deficiency Syndromes, Male, Metabolism, Inborn Errors, Mutation, Obesity, Pedigree, Phenotype, Receptors, Cell Surface, Age of Onset, Lymphocyte Count, Leptin, Receptors, Leptin
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