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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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 GPR54 gene as a regulator of puberty
Stephanie B. Seminara,Sophie Messager,Emmanouella E. Chatzidaki,Rosemary R. Thresher,James S. Acierno,Jenna K. Shagoury,Yousef Bo-Abbas,Wendy Kuohung,Kristine M. Schwinof,Alan G. Hendrick,Dirk Zahn,John Dixon,Ursula B. Kaiser,Susan A. Slaugenhaupt,James F. Gusella,Stephen O'Rahilly,Mark Carlton,William F. Crowley,Samuel Aparicio,William H. Colledge +19 more
TL;DR: Puberty is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus, and complementary genetic approaches in humans and mice identified genetic factors that determine the onset of puberty.
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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals
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TL;DR: A much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, can be much better translated to human health.
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Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
Sophie Messager,Emmanouella E. Chatzidaki,Dan Ma,Alan G. Hendrick,Dirk Zahn,John Dixon,Rosemary R. Thresher,Isabelle Malinge,Didier Lomet,Mark B. L. Carlton,William H. Colledge,Alain Caraty,Samuel Aparicio +12 more
TL;DR: GPR54 is defined as a major control point in the reproductive axis and kisspeptin is suggested to be a neurohormonal effector, demonstrating that a key action ofkisspeptin on the hypothalamo-pituitary-gonadal axis occurs directly at the level of GnRH release.
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A Role for Kisspeptins in the Regulation of Gonadotropin Secretion in the Mouse
Michelle L. Gottsch,Matthew Cunningham,Jeremy Troy Smith,Simina M. Popa,Blake V. Acohido,William F. Crowley,Stephanie B. Seminara,Donald K. Clifton,Robert A. Steiner +8 more
TL;DR: Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54, and it is concluded that kisspeptin-GPR54 signaling may be part of the hypothalamus circuitry that governs the hypothalamic secretion of GnRH.
References
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TL;DR: The goal of the present review is to specifically address the physical changes linking agonist binding to receptor activation and subsequent transduction of the signal to the associated G protein on the cytoplasmic side of the membrane and to other putative signaling pathways.
Journal ArticleDOI
KiSS-1, a Novel Human Malignant Melanoma Metastasis-Suppressor Gene
Jeong Hyung Lee,Mary E. Miele,Deana J. Hicks,Karen K. Phillips,Jeffery M. Trent,Bernard E. Weissman,Danny R. Welch +6 more
TL;DR: The results imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential of malignant melanoma cells and suggest that KiSS-1 expression may be a useful marker for distinguishing metastatic melanoma from nonmetastatic melanomas.
Journal ArticleDOI
AXOR12, a Novel Human G Protein-coupled Receptor, Activated by the Peptide KiSS-1
Alison I. Muir,Larissa Chamberlain,Nabil Elshourbagy,David Michalovich,Darren J. Moore,Amy Calamari,Philip G. Szekeres,Henry M. Sarau,Jon K. Chambers,Paul R. Murdock,Klaudia Steplewski,Usman Shabon,Jane E. Miller,Susan E. Middleton,John G. Darker,Christopher Larminie,Shelagh Wilson,Derk J. Bergsma,Piers C. Emson,Richard L.M. Faull,Karen L. Philpott,David C. Harrison +21 more
TL;DR: High potency agonism was evident from peptides derived from the gene KiSS-1, the expression of which prevents metastasis in melanoma cells, and the nature of the putative cognate ligand for AXOR12 are discussed.
Journal ArticleDOI
A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.
Brunella Franco,S Guioli,Antonella Pragliola,Antonella Pragliola,Barbara Incerti,Barbara Bardoni,Rossana Tonlorenzi,Romeo Carrozzo,Elena Maestrini,Maura Pieretti,Patricia Taillon-Miller,Carolyn J. Brown,Huntington F. Willard,Charles B. Lawrence,M. Graziella Persico,Giovanna Camerino,Andrea Ballabio +16 more
TL;DR: A gene has now been isolated from the critical region on Xp22.3 to which Kallmann's syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome, and shows an unusual pattern of conservation across species.
Journal ArticleDOI
Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.
Catherine Dodé,Jacqueline Levilliers,Jean-Michel Dupont,Anne De Paepe,Nathalie Le Dû,Nadia Soussi-Yanicostas,Roney S. Coimbra,Sedigheh Delmaghani,Sylvie Compain-Nouaille,Françoise Baverel,Christophe Pêcheux,Dominique Le Tessier,Corinne Cruaud,Marc Delpech,Frank Speleman,Stefan Vermeulen,Andrea Amalfitano,Yvan Bachelot,Philippe Bouchard,Sylvie Cabrol,Jean-Claude Carel,Henriette A. Delemarre-van de Waal,Barbara Goulet-Salmon,Marie-Laure Kottler,Odile Richard,Franco Sánchez-Franco,Robert Saura,Jacques Young,Christine Petit,Jean-Pierre Hardelin +29 more
TL;DR: It is established here that loss- of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation inFGFR1 has been shown to cause a form of craniosynostosis and suggested that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling.
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