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PMID:16511605

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Citation

Pantel, J, Legendre, M, Cabrol, S, Hilal, L, Hajaji, Y, Morisset, S, Nivot, S, Vie-Luton, MP, Grouselle, D, de Kerdanet, M, Kadiri, A, Epelbaum, J, Le Bouc, Y and Amselem, S (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J. Clin. Invest. 116:760-8

Abstract

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.

Links

PubMed PMC1386106 Online version:10.1172/JCI25303

Keywords

Adolescent; Adult; Amino Acid Sequence; Amino Acid Substitution/genetics; Animals; Body Height/genetics; Cell Line; Child; Female; Ghrelin; Growth Disorders/genetics; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Pedigree; Peptide Hormones/metabolism; Peptide Hormones/physiology; Receptors, G-Protein-Coupled/deficiency; Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/physiology; Receptors, Ghrelin

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GHRL

involved_in

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GHRL

involved_in

GO:0040018: positive regulation of multicellular organism growth

ECO:0000305: curator inference used in manual assertion

GO:0031768

P

Seeded From UniProt

complete

HUMAN:GHRL

involved_in

GO:0009755: hormone-mediated signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GHRL

enables

GO:0016608: growth hormone-releasing hormone activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GHRL

involved_in

GO:0030252: growth hormone secretion

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GHRL

enables

GO:0031768: ghrelin receptor binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GHSR

involved_in

GO:0030252: growth hormone secretion

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GHSR

involved_in

GO:0040018: positive regulation of multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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