Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature.
The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synthetic molecules endowed with GH release properties. As shown recently through in vitro means, this receptor displays a constitutive activity whose clinical relevance is unknown. Although pharmacological studies have demonstrated that its endogenous ligand--ghrelin--stimulates, through the GHSR, GH secretion and appetite, the physiological importance of the GHSR-dependent pathways remains an open question that gives rise to much controversy. We report the identification of a GHSR missense mutation that segregates with short stature within 2 unrelated families. This mutation, which results in decreased cell-surface expression of the receptor, selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin. This first description, to our knowledge, of a functionally significant GHSR mutation, which unveils the critical importance of the GHSR-associated constitutive activity, discloses an unusual pathogenic mechanism of growth failure in humans.
Pantel
Jacques
J
INSERM, U654, Centre Hospitalier Universitaire Henri-Mondor, Créteil, France. jacques.pantel@im3.inserm.fr
Legendre
Marie
M
Cabrol
Sylvie
S
Hilal
Latifa
L
Hajaji
Yassir
Y
Morisset
Séverine
S
Nivot
Sylvie
S
Vie-Luton
Marie-Pierre
MP
Grouselle
Dominique
D
de Kerdanet
Marc
M
Kadiri
Abdelkrim
A
Epelbaum
Jacques
J
Le Bouc
Yves
Y
Amselem
Serge
S
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001827:Body Height / Q000235:genetics*; D002460:Cell Line; D002648:Child; D005260:Female; D054439:Ghrelin; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D036361:Peptide Hormones / Q000378:metabolism / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D054440:Receptors, Ghrelin
D054439:Ghrelin; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin