Insights into the Molecular Basis of Kallman Syndrome


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.



Bulow HE, Berry KL, Topper LH, Peles E and Hobert O (2002) Heparan sulfate proteoglycan‐dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal‐1. Proceedings of the National Academy of Sciences of the USA 99: 6346–6351.

Bulow HE and Hobert O (2004) Differential sulfations and epimerization define heparan sulfate specificity in nervous system development. Neuron 41: 723–736.

Dode C, Levilliers J, Dupont JM et al. (2003) Loss‐of‐function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nature Genetics 33: 463–465.

Franco B, Guioli S, Pragliola A et al. (1991) A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path‐finding molecules. Nature 353: 529–536.

Gonzalez‐Martinez D, Kim SH, Hu Y et al. (2004) Anosmin‐1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin‐releasing hormone olfactory neuroblasts through a heparan sulfate‐dependent mechanism. Journal of Neuroscience 24: 10384–10392.

Hebert JM, Lin M, Partanen J, Rossant J and McConnell SK (2003) FGF signaling through FGFR1 is required for olfactory bulb morphogenesis. Development 130: 1101–1111.

Hu Y, Gonzalez‐Martinez D, Kim SH and Bouloux PM (2004) Cross‐talk of anosmin‐1, the protein implicated in X‐linked Kallmann's syndrome, with heparan sulphate and urokinase‐type plasminogen activator. Biochemical Journal 384: 495–505.

Hu Y, Sun Z, Eaton JT, Bouloux PM and Perkins SJ (2005) Extended and flexible domain solution structure of the extracellular matrix protein anosmin‐1 by X‐ray scattering, analytical ultracentrifugation and constrained modelling. Journal of Molecular Biology 350: 553–570.

Legouis R, Hardelin JP, Levilliers J et al. (1991) The candidate gene for the X‐linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67: 423–435.

MacColl G, Quinton R and Bouloux PM (2002) GnRH neuronal development: insights into hypogonadotrophic hypogonadism. Trends in Endocrinology and Metabolism 13: 112–118.

Oliveira LM, Seminara SB, Beranova M et al. (2001) The importance of autosomal genes in Kallmann syndrome: genotype–phenotype correlations and neuroendocrine characteristics. Journal of Clinical Endocrinology and Metabolism 86: 1532–1538.

Pitteloud N, Meysing A, Quinton R et al. (2006) Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Molecular and Cellular Endocrinology 254‐255: 60–69.

Schwanzel‐Fukuda M and Pfaff DW (1989) Origin of luteinizing hormone‐releasing hormone neurons. Nature 338: 161–164.

Soussi‐Yanicostas N, de Castro F, Julliard AK et al. (2002) Anosmin‐1, defective in the X‐linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons. Cell 109: 217–228.

Tsai PS, Moenter SM, Postigo HR et al. (2005) Targeted expression of a dominant‐negative fibroblast growth factor (FGF) receptor in gonadotropin‐releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Molecular Endocrinology 19: 225–236.

Whitlock KE, Illing N, Brideau NJ, Smith KM and Twomey S (2006) Development of GnRH cells: Setting the stage for puberty. Molecular and Cellular Endocrinology 254–255: 39–50.

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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. [doi: 10.1002/9780470015902.a0006100]