Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor
Of 300 persons selected for early-onset obesity, hyperphagia, and consanguineous parentage, 8 had mutations in the leptin-receptor gene ( LEPR ). Biochemical and clinical analyses of the affected subjects suggest that the assay of serum leptin levels is not an appropriate screening tool for LEPR mut...
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| Published in | The New England journal of medicine Vol. 356; no. 3; pp. 237 - 247 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Boston, MA
Massachusetts Medical Society
18.01.2007
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0028-4793 1533-4406 1533-4406 |
| DOI | 10.1056/NEJMoa063988 |
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| Abstract | Of 300 persons selected for early-onset obesity, hyperphagia, and consanguineous parentage, 8 had mutations in the leptin-receptor gene (
LEPR
). Biochemical and clinical analyses of the affected subjects suggest that the assay of serum leptin levels is not an appropriate screening tool for
LEPR
mutations and that the
LEPR
protein product may not be the only leptin receptor in humans.
Biochemical and clinical analyses suggest that the assay of serum leptin levels is not an appropriate screening tool for
LEPR
mutations and that the
LEPR
protein product may not be the only leptin receptor in humans.
The assessment of patients with severe early-onset obesity conventionally includes screening for potentially treatable neurologic and endocrine conditions and identifying known genetic conditions so that appropriate genetic counseling and, in some cases, treatment can be instituted.
1
Classically, patients with genetic obesity syndromes have been identified in childhood as a result of associated mental retardation and developmental abnormalities.
2
However, several monogenic disorders have been identified in which obesity itself is the predominant presenting feature. These disorders result from disruption of the hypothalamic leptin–melanocortin signaling pathway.
3
–
8
Twelve subjects with congenital leptin deficiency due to loss-of-function mutations in the gene encoding leptin . . . |
|---|---|
| AbstractList | Of 300 persons selected for early-onset obesity, hyperphagia, and consanguineous parentage, 8 had mutations in the leptin-receptor gene (
LEPR
). Biochemical and clinical analyses of the affected subjects suggest that the assay of serum leptin levels is not an appropriate screening tool for
LEPR
mutations and that the
LEPR
protein product may not be the only leptin receptor in humans.
Biochemical and clinical analyses suggest that the assay of serum leptin levels is not an appropriate screening tool for
LEPR
mutations and that the
LEPR
protein product may not be the only leptin receptor in humans.
The assessment of patients with severe early-onset obesity conventionally includes screening for potentially treatable neurologic and endocrine conditions and identifying known genetic conditions so that appropriate genetic counseling and, in some cases, treatment can be instituted.
1
Classically, patients with genetic obesity syndromes have been identified in childhood as a result of associated mental retardation and developmental abnormalities.
2
However, several monogenic disorders have been identified in which obesity itself is the predominant presenting feature. These disorders result from disruption of the hypothalamic leptin–melanocortin signaling pathway.
3
–
8
Twelve subjects with congenital leptin deficiency due to loss-of-function mutations in the gene encoding leptin . . . 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. 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. 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. 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. 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. 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.BACKGROUNDA 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.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.METHODSWe 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.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.RESULTSOf 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.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.CONCLUSIONSThe 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. |
| Author | Undlien, Dag E McKenzie, Sheila Kimber, Wendy De Rosa, Veronica Barroso, Inês Lessan, Nader Keogh, Julia M Myhre, Anne Grethe Ghodsi, Maryam Lank, Emma Bottomley, Bill Collins, Stephan Farooqi, I. Sadaf Retterstol, Lars Edge, Julie A Fontana, Silvia O'Rahilly, Stephen Lopez-Fernandez, Judith Stanhope, Richard Ercan, Oya Matarese, Giuseppe Ferraz-Amaro, Ivan Dattani, Mehul T Perna, Francesco Wangensteen, Teresia |
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| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18449059$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/17229951$$D View this record in MEDLINE/PubMed |
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| CODEN | NEJMAG |
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| Keywords | Medicine Symptomatology Congenital Deficiency Leptin Genetics Biological receptor |
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| Snippet | Of 300 persons selected for early-onset obesity, hyperphagia, and consanguineous parentage, 8 had mutations in the leptin-receptor gene (
LEPR
). Biochemical... 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,... 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... 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... |
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| SubjectTerms | Adult Age Age of Onset Basal Metabolism Biological and medical sciences Body Composition Child Diagnosis, Differential Female General aspects Genes Genetic counseling Genotype Humans Hyperphagia - blood Hyperphagia - complications Hyperphagia - genetics Hypogonadism - blood Hypogonadism - complications Hypogonadism - genetics Immunologic Deficiency Syndromes - blood Immunologic Deficiency Syndromes - complications Immunologic Deficiency Syndromes - genetics Leptin - blood Lymphocyte Count Male Medical sciences Metabolism, Inborn Errors - blood Metabolism, Inborn Errors - diagnosis Metabolism, Inborn Errors - genetics Mutation Obesity Obesity - blood Obesity - complications Obesity - genetics Original Pedigree Phenotype Receptors, Cell Surface - deficiency Receptors, Cell Surface - genetics Receptors, Leptin Studies |
| Title | Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor |
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