Severe early-onset obesity, adrenal insufficiency and red hair pigmentation
caused by POMC mutations in humans
Heiko Krude1, Heike Biebermann1, Werner Luck1, Rüdiger Horn2, Georg Brabant2
& Annette Grüters1
1
Department of Pediatrics, Charité, Campus Virchow,
Humboldt-University Berlin, Germany.
2
Department of Clinical Endocrinology, Medizinische
Hochschule Hannover, Germany.
Correspondence should be addressed to Annette Grüters grueters@ukrv.de
Sequential cleavage of the precursor protein pre−pro−opiomelanocortin
(POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte−stimulating
hormones (MSH) , , and as well as the opioid−receptor
ligand −endorphin1. 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 −MSH in the regulation of food intake
by activation of the brain melanocortin−4−receptor (MC4−R;
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 −MSH 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, C7133) which interfere with appropriate
synthesis of ACTH and -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 early−onset obesity,
adrenal insufficiency and red hair pigmentation.
, 
, and 
as well as the opioid−receptor
ligand 
) which interfere with appropriate
synthesis of ACTH and 
