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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WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
Hyung Goo Kim,Hyung Goo Kim,Hyung Goo Kim,Jang Won Ahn,Ingo Kurth,Reinhard Ullmann,Hyun Taek Kim,Anita S. Kulharya,Kyung Soo Ha,Yasuhide Itokawa,Irene Meliciani,Wolfgang Wenzel,Deresa Lee,Georg Rosenberger,Metin Ozata,David P. Bick,Richard J. Sherins,Takahiro Nagase,Mustafa Tekin,Mustafa Tekin,Soo-Hyun Kim,Cheol-Hee Kim,Hans-Hilger Ropers,James F. Gusella,Vera M. Kalscheuer,Cheol Yong Choi,Lawrence C. Layman +26 more
TL;DR: It is discovered that WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and that missense alterations reduce or abolish this interaction.
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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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Tetsuya Ohtaki,Yasushi Shintani,Susumu Honda,Hirokazu Matsumoto,Akira Hori,Kimiko Kanehashi,Yasuko Terao,Satoshi Kumano,Yoshihiro Takatsu,Yasushi Masuda,Yoshihiro Ishibashi,Takuya Watanabe,Mari Asada,Takao Yamada,Masato Suenaga,Chieko Kitada,Satoshi Usuki,Tsutomu Kurokawa,Haruo Onda,Osamu Nishimura,Masahiko Fujino +20 more
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