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Mechanisms of Disease: insights into X-linked and autosomal-dominant Kallmann syndrome

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 160–171 (2006)Cite this article

Abstract

Kallmann syndrome (KS) is a disorder characterized by hypogonadotropic hypogonadism and anosmia. Although KS is genetically heterogeneous, only two causal genes have been identified to date. These include an X-linked gene that encodes anosmin 1 and an autosomal gene that encodes fibroblast growth factor receptor 1. Mutations in these two genes result in disorders that often include, but are not limited to, severe defects in olfactory and reproductive functions. In this respect, KS can be regarded as a 'human model' for understanding critical factors that regulate olfactory and reproductive development. Here we give an overview of the disorders that stem from mutations in these two genes, with special emphasis on the cellular mechanisms underlying olfactory and reproductive anomalies. Other, less well-known aspects of KS, such as the convergence of symptoms in patients with different genetic forms of KS and the unpredictable manifestation of KS symptoms, are also discussed.

Key Points

  • Kallmann syndrome (KS) is characterized by hypogonaotropic hypogonadism and anosmia; it can occur sporadically or be inherited as X-linked, autosomal dominant or autosomal recessive forms

  • Mutations in KAL1, which encodes the glycoprotein anosmin-1 in embryonic extracellular matrix, cause the X-linked form

  • Limited human embryonic data indicate that KAL1 mutations lead to defects in gonadotropin-releasing hormone (GnRH) neuronal migration secondary to aberrant olfactory axon growth

  • Mutations in the gene encoding fibroblast growth factor receptor 1 (FGFR1) can cause the autosomal dominant form

  • Data from a transgenic mouse model indicate that mutations in FGFR1 can directly affect GnRH neuronal birth, migration, and axon targeting, leading to diverse defects in the GnRH system

  • Overall, mutations in these two genes account for 20% of KS, but the phenotype of KS is variable and cannot be predicted simply from knowledge of the mutated genes

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Figure 1: Diagrammatic representation of anosmin 1 and fibroblast growth factor receptor 1 protein structures
Figure 2: A schematic representation of the development of the olfactory system and gonadotropin-releasing hormone neurons in normal individuals and those with the X-linked form of Kallman syndrome
Figure 3: Representative photomicrographs of postnatal day 1 gonadotropin-releasing hormone neurons at the intrahemispheric area dorsal to the cribriform plate

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Acknowledgements

This work was supported by NIH grants RO1 HD042634 and F31 HD47991.

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  1. P-S Tsai is an assistant professor, and JC Gill is a PhD candidate

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  1. the Department of Integrative Physiology, University of Colorado at Boulder, CO, USA

    Pei-San Tsai & John C Gill

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Tsai, PS., Gill, J. Mechanisms of Disease: insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Rev Endocrinol 2, 160–171 (2006). https://doi.org/10.1038/ncpendmet0119

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