Molecular Pathogenesis of Kallmanns Syndrome

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 -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 Xlinked 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 urokinasetype plasminogen activator and FGFR1. It has previously been shown that anosmin-1 enhances FGFR1 signalling in a heparan sulphate-dependent manner, and proposed that Published online: December 21, 2006 HORMONE RESEARCH Steven Cadman Centre for Neuroendocrinology, Royal Free and University College Medical School Rowland Hill Street London NW3 2PF (UK) Tel. +44 020 7433 2879, Fax +44 020 7433 2871, E Mail s.cadman@medsch.ucl.ac.uk © 2007 S. Karger AG, Basel 0301–0163/07/0675–0231$23.50/0 Accessible online at: www.karger.com/hre D ow nl oa de d by : 15 7. 55 .3 9. 42 4 /2 1/ 20 16 7 :5 1: 26 A M