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 proteincoupled 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.
Complementary DNA clones, encoding the LH-hCG (luteinizing hormone-human choriogonadotropic hormone) receptor were isolated by screening a lambda gt11 library with monoclonal antibodies. The primary structure of the protein was deduced from the DNA sequence analysis; the protein contains 696 amino acids with a putative signal peptide of 27 amino acids. Hydropathy analysis suggests the existence of seven transmembrane domains that show homology with the corresponding regions of other G protein-coupled receptors. Three other types of clones corresponding to shorter proteins were observed, in which the putative transmembrane domain was absent. These probably arose through alternative splicing. RNA blot analysis showed similar patterns in testis and ovary with a major RNA of 4700 nucleotides and several minor species. The messenger RNA was expressed in COS-7 cells, yielding a protein that bound hCG with the same affinity as the testicular receptor.
Letter to the Editor this criteria correspond to known functional groups of A Unified Nomenclature System for receptors. This procedure yields six subfamilies. All the the Nuclear Receptor Superfamily unusual receptors that contain only one of the two conserved domains (C or E) were grouped into a separate subfamily (subfamily 0) irrespective of their evolutionary Nuclear hormone receptors (NRs) are important tranorigin. Within subfamilies, groups of receptors are descriptional regulators involved in widely diverse physiofined as the most internal branches with bootstrap vallogical functions such as control of embryonic developues above 90%. In this nomenclature system, the numment, cell differentiation, and homeostasis (Gronemeyer ber of a given receptor inside a group does not carry and Laudet, 1995; Mangelsdorf et al., 1995). In addition, any specific information. In many cases these groups these molecules are extremely important in medical recontain arthropod and vertebrate members. The various search since a large number of them are implicated in homologs of the same gene in invertebrates (e.g., Drodiseases such as cancer, diabetes, or hormone resissophila and Caenorhabditis) have the same name. It is tance syndromes. Some of the NRs act as ligand-inducible transcription factors, while a large number of them have no defined ligand and are hence described as "orphan" receptors (Enmark and Gustafsson, 1996). Over the last decade, workers in the field have described more than 300 sequences of NRs using an increasingly complex and baroque nomenclature. The existence of several names for the same gene is an acute problem for the orphan receptors, which often cannot be described by their function, particularly at the moment of their discovery. As discussed during the Seventh International CBT Symposium on "Nuclear Orphan Receptors" in Huddinge, Sweden (September 9-12, 1995), this plethora of names has become more and more confusing and now constitutes a barrier for understanding of newly acquired knowledge to researchers outside as well as within the field. For that reason, four of us (V. L., J. A., J.-A. G., and W. W.) agreed to form a committee for the nomenclature of NRs. It is the purpose of this paper to recommend names for the subfamilies and groups of receptors based on a phylogenetic tree connecting all known NR sequences. This system, based on the evolution of the two well-conserved domains of NRs (the DNA-binding C domain and the ligand-binding E domain), offers a practical and significant framework to which subsequent genes can be easily added. The resulting nomenclature has now been endorsed by over 40 scientists 1 many of whom contributed to defining the nomenclature and to preparing this letter. This nomenclature has been discussed with the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR). A subcommittee of NC-IUPHAR entitled "Nuclear Receptors" will be set up to further clarify receptor nomenclature to integrate structure and function.A summa...
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