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      Invertebrate Models of Kallmann Syndrome: Molecular Pathogenesis and New Disease Genes

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          Abstract

          Kallmann Syndrome is a heritable disorder characterized by congenital anosmia, hypogonadotropic hypogonadism and, less frequently, by other symptoms. The X-linked form of this syndrome is caused by mutations affecting the KAL1 gene that codes for the extracellular protein anosmin-1. Investigation of KAL1 function in mice has been hampered by the fact that the murine ortholog has not been identified. Thus studies performed in other animal models have contributed significantly to an understanding of the function of KAL1. In this review, the main results obtained using the two invertebrate models, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, are illustrated and the contribution provided by them to the elucidation of the molecular pathogenesis of Kallmann Syndrome is discussed in detail. Structure-function dissection studies performed in these two animal models have shown how the different domains of anosmin-1 carry out specific functions, also suggesting a novel intramolecular regulation mechanism among the different domains of the protein. The model that emerges is one in which anosmin-1 plays different roles in different tissues, interacting with different components of the extracellular matrix. We also describe how the genetic approach in C. elegans has allowed the discovery of the genes involved in KAL1-heparan sulfate proteoglycans interactions and the identification of HS6ST1 as a new disease gene.

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          Most cited references69

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          Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.

          In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1-4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1-9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10-23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity.
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            Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.

            We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.
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              A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.

              Kallmann's syndrome (clinically characterized by hypogonadotropic hypogonadism and inability to smell) is caused by a defect in the migration of olfactory neurons, and neurons producing hypothalamic gonadotropin-releasing hormone. A gene has now been isolated from the critical region on Xp22.3 to which the syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome, and shows an unusual pattern of conservation across species. The predicted protein has significant similarities with proteins involved in neural cell adhesion and axonal pathfinding, as well as with protein kinases and phosphatases, which suggests that this gene could have a specific role in neuronal migration.
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                Author and article information

                Journal
                Curr Genomics
                Curr. Genomics
                CG
                Current Genomics
                Bentham Science Publishers
                1389-2029
                1875-5488
                March 2013
                March 2013
                : 14
                : 1
                : 2-10
                Affiliations
                Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy
                Author notes
                [* ]Address correspondence to this author at the Institute of Genetics and Biophysics, Consiglio Nazionale delle ricerche (CNR), via Pietro Castellino 111, 80131 Naples, Italy; Tel: +39-081-6132355; Fax: +39-081-6132706; E-mail: davide.andrenacci@ 123456igb.cnr.it
                Article
                CG-14-2
                10.2174/138920213804999174
                3580776
                23997646
                2c48cee7-d66d-470a-84e8-0ec2e5d24a68
                ©2013 Bentham Science Publishers

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 May 2012
                : 8 October 2012
                : 8 October 2012
                Categories
                Article

                Genetics
                animal models,axon branching,cekal-1,dmkal-1,extracellular matrix.,morphogenesis
                Genetics
                animal models, axon branching, cekal-1, dmkal-1, extracellular matrix., morphogenesis

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