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
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The Kisspeptin/Neurokinin B/Dynorphin (KNDy) Cell Population of the Arcuate Nucleus: Sex Differences and Effects of Prenatal Testosterone in Sheep
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Isolated Familial Hypogonadotropic Hypogonadism and a GNRH1 Mutation
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TL;DR: A homozygous GNRH1 frameshift mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro.
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Epigenetic control of female puberty
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TL;DR: This work shows that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats and identifies silencers of the Polycomb group (PcG) as principal contributors to this mechanism and shows that PcG proteins repress Kiss1, a puberty-activating gene.
Journal ArticleDOI
Expression of KiSS-1 in Rat Ovary: Putative Local Regulator of Ovulation?
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Journal ArticleDOI
Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels.
TL;DR: Electrophysiology and calcium imaging studies indicate that kisspeptin activates G protein-coupled receptor 54 (GPR54) to initiate a PLC-IP3R-calcium cascade that modulates both potassium and NSC channels to initiate depolarization in GnRH neurons.
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