title: Molecular pathogenesis of Kallmann's syndrome.
abstract: Hypogonadotrophic hypogonadism (HH) is characterized by delayed or absent pubertal development secondary to gonadotrophin deficiency. HH can result from mutations of the gonadotrophin-releasing hormone receptor 1, the gonadotrophin beta-subunits, or various transcription factors involved in pituitary gland development. HH occurs in DAX1 mutations when associated with adrenal insufficiency (adrenal hypoplasia congenita), and is also linked with obesity in patients with mutations of leptin and its receptor, as well as mutations in prohormone convertase 1. Rarely, HH has resulted from kisspeptin receptor (GPR54) mutations, a gene implicated in the regulation of pubertal onset. When occurring with anosmia (a lack of sense of smell), HH is referred to as Kallmann's syndrome (KS). Two KS-related loci are currently known: KAL1, encoding anosmin-1, responsible for X-linked KS, and KAL2, encoding the fibroblast growth factor receptor 1 (FGFR1), mutated in autosomal dominant KS. Anosmin-1 is an extracellular glycoprotein with some unique structural characteristics; it interacts with both urokinase-type plasminogen activator and FGFR1. It has previously been shown that anosmin-1 enhances FGFR1 signalling in a heparan sulphate-dependent manner, and proposed that anosmin-1 fine-tunes FGFR1 signalling during olfactory and GnRH neuronal development. Here, we review the known normosmic causes of HH, and discuss novel developmental and molecular mechanisms underlying KS; finally, we introduce three novel genes (NELF, PKR2, and CHD7) that may be associated with some phenotypic features of KS.
authors.affiliation: Centre for Neuroendocrinology, Royal Free and University College Medical School, University College London, London, UK. s.cadman@medsch.ucl.ac.uk
authors.forename: Steven Mark
authors.initials: SM
authors.lastname: Cadman
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Youli
authors.initials: Y
authors.lastname: Hu
authors.forename: David
authors.initials: D
authors.lastname: González-Martínez
authors.forename: Pierre-Marc
authors.initials: PM
authors.lastname: Bouloux
mesh_terms: D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant; D050172:Genes, X-Linked; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology; D006801:Humans; D017436:Kallmann Syndrome / Q000209:etiology* / Q000235:genetics*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009830:Olfactory Bulb / Q000196:embryology / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000502:physiology; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D019812:Heparan Sulfate Proteoglycans; D009419:Nerve Tissue Proteins; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1