Abstract
Sequential cleavage of the precursor protein preâproâopiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyteâstimulating hormones (MSH) α, β, and γ as well as the opioidâreceptor ligand βâendorphin1. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far2. Recent studies in animal models elucidated a central role of αâMSH in the regulation of food intake by activation of the brain melanocortinâ4âreceptor (MC4âR; refs 3, 4, 5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus6, led to the proposal of an association of POMC with human obesity7.The dual role of αâMSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133Î) which interfere with appropriate synthesis of ACTH and α-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in earlyâonset obesity, adrenal insufficiency and red hair pigmentation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Smith, A.I. Funder, J.W. Proopiomelanocortin processing in the pituitary, central nervous system and peripheral tissues. Endocr. Rev. 9, 159â179 ( 1988).
Nussey, S.S. et al. Isolated congenital ACTH deficiency: A cleavage enzyme defect? Clin. Endocr. 39, 381â385 (1993).
Lu, D. et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371, 799â802 ( 1994).
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131â141 (1997).
Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J. Cone, R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165â168 (1997).
Comuzzie, A.G. et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genet. 15, 273â275 (1997).
Seeley, R.J. et al. Melanocortin receptors in leptin effects. Nature 390 , 349 (1997).
Takahashi, H. et al. Complete nucleotide sequence of the human corticotropin-lipoprotein precursor gene. Nucleic Acids Res. 11, 6847â6858 (1983).
Takahashi, H., Teranishi, Y., Nakanishi, S. Huma, S. Isolation and structural organization of the human corticotropin-lipotropin precursor gene. FEBS Lett. 135, 97â102 ( 1981).
Kozak, M. The scanning model for translation: an update. J. Cell Biol. 108, 229â241 (1989).
Kozak, M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eucaryotic ribosomes. Cell 44, 283â292 (1986).
Morle, F., Lopez, B., Henni, T. Godet, J. α-thalassaemia associated with the deletion of two nucleotides at position -2 and -3 preceding the AUG codon. EMBO J. 4, 1245â1250 (1985).
Rutishauser, J. et al. A novel point mutation in the translation initiation codon of the pre-pro-vasopressin-neurophysin II gene: cosegragtion with morphological abnormalities and clinical symptoms in autosomal dominant neurohypophyseal diabetes insipidus. J. Clin. Endcrinol. Metab. 81, 192â198 (1996).
Bergenheim, N.C.H., Venta, P.J., Hopkins, P.J., Kim, H.J. Tashian, R.E. Mutation creates an open reading frame within the 5`untranslated region of macaque erythrocyte carbonic anhydrase (CA) I mRNA that suppresses CA I expression and supports the scanning model for translation. Proc. Natl. Acad. Sci. USA 89, 8798â8802 (1992).
Siracusa, L.D. The agouti gene: turned on to yellow. Trends Genet. 10, 423â428 (1994).
Klungland, H., Vage, D.I., Gomez-Raya, L., Adalsteinsson, S. Lien, S. The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination. Mamm. Genome 6, 636â639 (1995).
Joerg, H., Fries, H.R., Meijernik, E. Stranzinger, G.F. Red coat color in Holstein cattle is associated with a deletion in the MSHR gene. Mamm. Genome 7, 317â318 ( 1996).
Valverde, P., Healy, E., Jackson, I., Rees, J.L. Thody, A.J. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genet. 11, 328â330 (1995).
Box, N.F., Wyeth, J.R., O'Gorman, L.E., Martin, N.G. Sturm, R.A. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum. Mol. Genet. 6, 1891â1897 ( 1997).
Cone, R.D. et al. The melanocortin receptors: agonists, antagonists and the hormonal control of pigmentation. Rec. Prog. Horm. Res. 51, 287â318 (1996).
Jackson, R.S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genet. 16 , 303â306 (1997).
Chen, W. et al. Exocrine gland dysfunction in MC5-R deficient mice: evidence for coordinated regulation of exocrine gland function by melanocorin peptides. Cell 91, 789â798 ( 1997).
Montague, C.T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903â908 (1997).
Strobel, A., Issad, T., Camoin, L., Ozata, M. Strosberg, A.D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genet. 18, 213 â215 (1998).
Clement, K. et al. A mutation in the human leptin receptor gene caused obesity and pituitary dysfunction. Nature 392, 398â401 (1998).
Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl. Acad. Sci. USA 86, 2766â2770 (1989).
Acknowledgements
The authors thank S. Schwarz for helpful discussions and K. Huhne for excellent technical assistance. This study was supported by a grant from the Deutsche Forschungsgemeinschaft to H.K. (Kr1710-1/1) and the Sonnenfeld-Stiftung to H.B.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Krude, H., Biebermann, H., Luck, W. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19, 155â157 (1998). https://doi.org/10.1038/509
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/509
This article is cited by
-
Diagnosis and management of secondary adrenal crisis
Reviews in Endocrine and Metabolic Disorders (2024)
-
Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus
Acta Neuropathologica Communications (2023)
-
Metabolic and feeding adjustments during pregnancy
Nature Reviews Endocrinology (2023)
-
The melanocortin action is biased toward protection from weight loss in mice
Nature Communications (2023)
-
The bi-directional association between bipolar disorder and obesity: Evidence from Meta and bioinformatics analysis
International Journal of Obesity (2023)