Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
Nicolas de Roux,Emmanuelle Génin,Jean Claude Carel,Fumihiko Matsuda,Chaussain Jl,Edwin Milgrom +5 more
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TLDR
The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR 54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.Abstract:
Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.read more
Citations
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A new key neurohormone controlling reproduction, gonadotropin-inhibitory hormone (GnIH): Biosynthesis, mode of action and functional significance
TL;DR: The advances made in the understanding of the biosynthesis, mode of action and functional significance of GnIH, a newly discovered key neurohormone, and its homologous peptides are summarized.
Journal ArticleDOI
The role of kisspeptin in the control of gonadotrophin secretion
TL;DR: Findings in the KiSS-1/gpr-54 system are highlighted, focusing on their regulation of the HPG axis in male and female reproductive systems of both mammalian and non-mammalian vertebrates.
Journal ArticleDOI
Discovery and evolutionary history of gonadotrophin-inhibitory hormone and kisspeptin: new key neuropeptides controlling reproduction.
Kazuyoshi Tsutsui,George E. Bentley,Lance J. Kriegsfeld,Tomohiro Osugi,Jae Young Seong,Hubert Vaudry +5 more
TL;DR: The KiSS‐1 gene is also highly conserved and has been identified in mammals, amphibians and fish, but not birds, rodents or primates.
Journal ArticleDOI
Kisspeptin is present in ovine hypophysial portal blood but does not increase during the preovulatory luteinizing hormone surge: evidence that gonadotropes are not direct targets of kisspeptin in vivo.
TL;DR: The low concentrations of kisspeptin in hypophysial portal blood and the lack of any change during the period of an estrogen-induced GnRH/LH surge suggest that action on the pituitary gland is not of major consequence in terms of LH release.
Journal ArticleDOI
GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism
Yee-Ming Chan,Adelaide De Guillebon,Mariarosaria Lang-Muritano,Lacey Plummer,Felecia Cerrato,Sarah Tsiaras,Ariana Gaspert,Helene B. Lavoie,Ching Hui Wu,William F. Crowley,John K. Amory,Nelly Pitteloud,Stephanie B. Seminara +12 more
TL;DR: DNA screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1 and establish mutations in GN RH1 as a genetic cause of nIHH.
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The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54.
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