| Structural highlights
Disease
KALM_HUMAN Defects in KAL1 are the cause of hypogonadotropic hypogonadism 1 with or without anosmia (HH1) [MIM:308700. A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Function
KALM_HUMAN Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex (By similarity). Chemoattractant for fetal olfactory epithelial cells.[14]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Kallmann's syndrome corresponds to a loss of sense of smell and hypogonadotrophic hypogonadism. Defects in anosmin-1 result in the X-linked inherited form of Kallmann's syndrome. Anosmin-1 is an extracellular matrix protein comprised of an N-terminal, cysteine-rich (Cys-box) domain and a whey acidic protein-like (WAP) domain, followed by four fibronectin type III (FnIII) domains. The solution structures of recombinant proteins containing the first three domains (PIWF1) and all six domains (PIWF4) were determined by X-ray scattering and analytical ultracentrifugation. Guinier analyses showed that PIWF1 and PIWF4 have different radii of gyration (R(G)) values of 3.1 nm and 6.7 nm, respectively, but similar cross-sectional radii of gyration (R(XS)) values of 1.5 nm and 1.9 nm, respectively. Distance distribution functions showed that the maximum lengths of PIWF1 and PIWF4 were 11 nm and 23 nm, respectively. Analytical ultracentrifugation gave sedimentation coefficients of 2.52 S and 3.55 S for PIWF1 and PIWF4, respectively. The interpretation of the scattering data by constrained modelling requires homology models for all six domains in anosmin-1. While models were already available for the WAP and FnIII domains, searches suggested the Cys-box domain may resemble the cysteine-rich region of the insulin-like growth factor receptor. Automated constrained molecular modelling based on joining the anosmin-1 domains with structurally randomised linkers resulted in 10,000 models for anosmin-1. A trial-and-error search showed that about 0.1-1.4% of these models fitted the X-ray data. The best models showed that the three domains and six domains in PIWF1 and PIWF4, respectively, were extended. The inter-domain linkers in anosmin-1 could not all be extended at the same time, and there was evidence for inter-domain flexibility. Models with folded-back domain arrangements do not fit the data. These solution structures account for the known biological function of anosmin-1, in particular its ability to interact with its three macromolecular ligands.
Extended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering, analytical ultracentrifugation and constrained modelling.,Hu Y, Sun Z, Eaton JT, Bouloux PM, Perkins SJ J Mol Biol. 2005 Jul 15;350(3):553-70. PMID:15949815[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim SH, Bouloux PM. Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1. J Biol Chem. 2009 Oct 23;284(43):29905-20. doi: 10.1074/jbc.M109.049155. Epub, 2009 Aug 20. PMID:19696444 doi:10.1074/jbc.M109.049155
- ↑ Hardelin JP, Levilliers J, Blanchard S, Carel JC, Leutenegger M, Pinard-Bertelletto JP, Bouloux P, Petit C. Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum Mol Genet. 1993 Apr;2(4):373-7. PMID:8504298
- ↑ Georgopoulos NA, Pralong FP, Seidman CE, Seidman JG, Crowley WF Jr, Vallejo M. Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency. J Clin Endocrinol Metab. 1997 Jan;82(1):213-7. PMID:8989261
- ↑ Maya-Nunez G, Zenteno JC, Ulloa-Aguirre A, Kofman-Alfaro S, Mendez JP. A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann's syndrome. J Clin Endocrinol Metab. 1998 May;83(5):1650-3. PMID:9589672
- ↑ Oliveira LM, Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, Costa EM, Latronico AC, Crowley WF Jr, Vallejo M. The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab. 2001 Apr;86(4):1532-8. PMID:11297579
- ↑ Cariboni A, Pimpinelli F, Colamarino S, Zaninetti R, Piccolella M, Rumio C, Piva F, Rugarli EI, Maggi R. The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet. 2004 Nov 15;13(22):2781-91. Epub 2004 Oct 7. PMID:15471890 doi:10.1093/hmg/ddh309
- ↑ Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S, Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, Nagasaki K, Hasegawa D, Hasegawa Y, Tachibana K, Naiki Y, Horikawa R, Tanaka T, Ogata T. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab. 2004 Mar;89(3):1079-88. PMID:15001591
- ↑ Albuisson J, Pecheux C, Carel JC, Lacombe D, Leheup B, Lapuzina P, Bouchard P, Legius E, Matthijs G, Wasniewska M, Delpech M, Young J, Hardelin JP, Dode C. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum Mutat. 2005 Jan;25(1):98-9. PMID:15605412 doi:10.1002/humu.9298
- ↑ Dode C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc JE, Wolczynski S, Delpech M, Petit C, Young J, Hardelin JP. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006 Oct 20;2(10):e175. Epub 2006 Sep 1. PMID:17054399 doi:06-PLGE-RA-0108R3
- ↑ Versiani BR, Trarbach E, Koenigkam-Santos M, Dos Santos AC, Elias LL, Moreira AC, Latronico AC, de Castro M. Clinical assessment and molecular analysis of GnRHR and KAL1 genes in males with idiopathic hypogonadotrophic hypogonadism. Clin Endocrinol (Oxf). 2007 Feb;66(2):173-9. PMID:17223984 doi:10.1111/j.1365-2265.2006.02702.x
- ↑ Bhagavath B, Xu N, Ozata M, Rosenfield RL, Bick DP, Sherins RJ, Layman LC. KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans. Mol Hum Reprod. 2007 Mar;13(3):165-70. Epub 2007 Jan 9. PMID:17213338 doi:gal108
- ↑ Zhang S, Wang T, Yang J, Liu Z, Wang S, Liu J. A fertile male patient with Kallmann syndrome and two missense mutations in the KAL1 gene. Fertil Steril. 2011 Apr;95(5):1789.e3-6. doi: 10.1016/j.fertnstert.2010.11.045., Epub 2010 Dec 18. PMID:21168128 doi:10.1016/j.fertnstert.2010.11.045
- ↑ Jap TS, Chiu CY, Lirng JF, Won GS. Identification of two novel missense mutations in the KAL1 gene in Han Chinese subjects with Kallmann Syndrome. J Endocrinol Invest. 2011 Jan;34(1):53-9. doi: 10.3275/7103. Epub 2010 Jun 4. PMID:20530987 doi:10.3275/7103
- ↑ Hu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim SH, Bouloux PM. Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1. J Biol Chem. 2009 Oct 23;284(43):29905-20. doi: 10.1074/jbc.M109.049155. Epub, 2009 Aug 20. PMID:19696444 doi:10.1074/jbc.M109.049155
- ↑ Hu Y, Sun Z, Eaton JT, Bouloux PM, Perkins SJ. Extended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering, analytical ultracentrifugation and constrained modelling. J Mol Biol. 2005 Jul 15;350(3):553-70. PMID:15949815 doi:http://dx.doi.org/10.1016/j.jmb.2005.04.031
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