Insights into the Molecular Basis of Kallman Syndrome

Abstract

Kallmann syndrome (KS) consists of anosmia related to defective olfactory bulb development and hypogonadotrophic hypogonadism due to gonadotrophin‐releasing hormone (GnRH) deficiency. Two genes have been identified so far: KAL‐1, encoding anosmin‐1, and KAL‐2,encoding fibroblast growth factor receptor 1 (FGFR1).

Keywords: Kallmann syndrome; hypogonadotrophic hypogonadism; anosmin‐1; fibroblast growth factor receptor 1

Figure 1.

(a) Domain structure of anosmin‐1. Residue numbering indicates the size of each of the six domains, N‐terminal signal peptide (SP) and C‐terminal histidine‐rich region (H), respectively. The residue length (bracketed) of linker between the six domains is arrowed. The location of six putative N‐glycosylation sites is indicated by numbered Y symbols. (b) The multidomain solution structure of anosmin‐1. The arrangement of the six domains of anosmin‐1 was extended with inter‐domain flexibility. The domains are coloured as follows: Cys box, blue; WAP, green; FnIII‐1 yellow; FnIII‐2, red; FnIII‐3, dark blue; FnIII‐4, orange. Cys box, cysteine rich region; WAP, whey acidic protein‐like four‐disulfide core motif; FnIII, fibronectin type III domain.

Figure 2.

Domain structure of FGFR1. The FGF ligand and heparan sulfate (HS) cofactor are shown interacting with FGFR1 at the top of the diagram. SP, signal peptide; D1, D2, D3, the three immunoglobulin‐like domains; AB, acid box; IIIb/IIIc, two major splicing isoforms; TM, transmembrane helix; PTK, the intracellular protein tyrosine kinase domain.

Figure 3.

A molecular model of anosmin‐1 interacting with the FGFR1 signalling complex. Anosmin‐1 further stabilizes extracellular ternary complex formation of FGFR1/FGF/HS to activate the transduction of intracellular downstream signalling, involving p42/44 and p38 for neurite outgrowth and Cdc42/Rac for cytoskeletal rearrangement.

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Hu, Youli, Kim, Soo‐Hyun, Cadman, Steven Mark, and Bouloux, Pierre‐Marc(Sep 2007) Insights into the Molecular Basis of Kallman Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006100]