Mini Review

Molecular Pathogenesis of Kallmann's Syndrome
Steven Mark Cadman^a, Soo-Hyun Kim^a, Youli Hu^a, David González-Martínez^{a, b}, Pierre-Marc Bouloux<sup>a

a</sup>Centre for Neuroendocrinology, Royal Free and University College Medical School, University College London, London, UK, and
^bResearch Group in Behavioral Neuroendocrinology, Center for Cellular and Molecular Neurobiology, University of Liège, Liège, Belgium

Address of Corresponding Author

Horm Res 2007;67:231-242 (DOI: 10.1159/000098156)

  Key Words

• Hypogonadotrophic hypogonadism
• Kallmann's syndrome
• Anosmin-1
• FGFR1
• CHD7
• NELF
• PKR2
• GPR54

  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 -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.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

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

  Article Information

Published online: December 21, 2006
Number of Print Pages : 12
Number of Figures : 5, Number of Tables : 1, Number of References : 84