Conclusion

GPR54 and its endogenous ligand, kisspeptin, are key regulators of the reproductive cascade. The discovery of loss-of-function and gain-of-function mutations in GPR54 in patients with idiopathic hypogonadotropic hypogonad-ism and central precocious puberty, respectively, has uncovered the fundamental role of the GPR54 pathway in the physiologic regulation of puberty and reproduction. Expression and pharmacologic studies establish the role of the GPR54 pathway in the stimulation of GnRH neurons during puberty. In the future, modulators of GPR54 activity and the super agonists of kisspeptin may prove valuable in clinical application in the fields of reproductive medicine in both animals and humans.

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Diseases Associated with Growth Hormone-Releasing Hormone Receptor (GHRHR) Mutations

Marco Martari and Roberto Salvatori

School of Medicine, Division of Endocrinology and Metabolism, Johns Hopkins University, Baltimore, Maryland 21287

I. Introduction 58

II. GHRHR Biology 60

A. GHRHR and Its Ligand 60

B. Signal Transduction 61

C. GHRHR Structure 62

D. GHRHR Organization and Regulation 64

E. GHRHR Splice Variants 65

III. GHRHR Mutations and Polymorphisms 66

A. GHRHR Mutations 66

B. GHRHR Polymorphisms 70

IV. Diseases Associated with GHRHR Mutations 70

A. Clinical Characteristics of Homozygous Individuals 70

B. Clinical Characteristics of Heterozygous Carriers 73

V. Conclusions 74

References 75

The growth hormone (GH)-releasing hormone (GHRH) receptor (GHRHR) belongs to the G protein-coupled receptors family. It is expressed almost exclusively in the anterior pituitary, where it is necessary for somatotroph cells proliferation and for GH synthesis and secretion. Mutations in the human GHRHR gene (GHRHR) can impair ligand binding and signal transduction, and have been estimated to cause about 10% of autosomal recessive familial isolated growth hormone deficiency (IGHD). Mutations reported to date include five splice donor site mutations, two microdeletions, two nonsense mutations, seven missense mutations, and one mutation in the promoter. These mutations have an autosomal recessive mode of inheritance, and heterozygous individuals do not show signs of IGHD, although the presence of an intermediate phenotype has been hypothesized. Conversely, patients with biallelic mutations have low serum insulin-like growth factor-1 and GH levels (with absent or reduced GH response to exogenous stimuli),

Progress in Molecular Biology and Translational Science, Vol. 88 DOI: 10.1016/S1877-1173(09)88003-4

Copyright 2009, Elsevier Inc.

All rights reserved. 1877-1173/09 $35.00

resulting—if not treated—in proportionate dwarfism. This chapter reviews the biology of the GHRHR, the mutations that affect its gene and their effects in homozygous and heterozygous individuals.

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