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Gene Review

KAL1  -  Kallmann syndrome 1 sequence

Homo sapiens

Synonyms: ADMLX, Adhesion molecule-like X-linked, Anosmin-1, HH1, HHA, ...
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Disease relevance of KAL1

  • The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons [1].
  • Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males [2].
  • Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction [2].
  • We characterized the clinical findings and molecular analysis of GnRHR and KAL1 genes in 26 Brazilian males with IHH with and without hyposmia/anosmia [3].
  • Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation [4].

Psychiatry related information on KAL1


High impact information on KAL1


Chemical compound and disease context of KAL1


Biological context of KAL1

  • Deletions or point mutations of a gene located at Xp22.3 (KAL1) are responsible for the disease [1].
  • PCR of the 14 exons of the KAL1 gene was performed on genomic DNA [15].
  • The duplication of nucleotides in exon 1 is located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or stopping the translation at the stop codon [15].
  • The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991 [16].
  • KAL1 encodes anosmin-1, an approximately 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis [16].

Anatomical context of KAL1


Associations of KAL1 with chemical compounds

  • Coexistence of Kallmann syndrome and complete androgen insensitivity in the same patient [18].
  • The proband presented at age 18 yr with KS and was subsequently treated with testosterone (T) therapy [19].
  • Finally, anosmin-1 (the product of the gene responsible of the X-linked form of Kallmann's disease) was found to induce a significant chemotactic response of GN11 cells, confirming a permissive/instructive role of KAL1 gene product in the migratory behaviour of GnRH neurons [20].
  • In addition, the combination of CADA with the gp41 fusion inhibitor T-20 (enfuvirtide), the CXCR4 antagonist AMD3100 and the gp120-specific interacting plant lectins from Galanthus nivalis (GNA) and Hippeastrum hybrid (HHA) also resulted in a synergistic inhibition [21].
  • CONCLUSIONS: A patient bearing a contiguous gene syndrome with partial deletion of the Kallmann syndrome gene and complete deletion of the steroid sulphatase gene is described [22].

Physical interactions of KAL1


Regulatory relationships of KAL1

  • FGFR1 loss-of-function mutations were reported in Kallmann syndrome whereas inactivating mutations of GPR54 were described in the idiopathic form of the gonadotropic deficiency [24].

Other interactions of KAL1

  • The last novel mutation, a stop codon in exon 6, is located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein [15].
  • Clinical assessment and molecular analysis of GnRHR and KAL1 genes in males with idiopathic hypogonadotrophic hypogonadism [3].
  • In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual [25].
  • 3. Four human YAC libraries were screened initially with sequences from DXS237 (GMGX9), DXS278 (S232B), and KAL and later with primers from exon 10 of the STS gene and the end fragment of a YAC clone YGX3 to fill the gaps [26].
  • The gene for the X-linked Kallmann syndrome (KAL), a developmental disorder characterized by hypogonadotropic hypogonadism and anosmia, maps to Xp22.3 and has a homologous locus, KALP, on Yq11 [27].

Analytical, diagnostic and therapeutic context of KAL1


  1. The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Cariboni, A., Pimpinelli, F., Colamarino, S., Zaninetti, R., Piccolella, M., Rumio, C., Piva, F., Rugarli, E.I., Maggi, R. Hum. Mol. Genet. (2004) [Pubmed]
  2. 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. 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. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  3. Clinical assessment and molecular analysis of GnRHR and KAL1 genes in males with idiopathic hypogonadotrophic hypogonadism. Versiani, B.R., Trarbach, E., Koenigkam-Santos, M., Dos Santos, A.C., Elias, L.L., Moreira, A.C., Latronico, A.C., de Castro, M. Clin. Endocrinol. (Oxf) (2007) [Pubmed]
  4. Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation. Weissörtel, R., Strom, T.M., Dörr, H.G., Rauch, A., Meitinger, T. Clin. Genet. (1998) [Pubmed]
  5. Hormones, genes, and behavior. Pfaff, D.W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  6. The Kallmann's syndrome variant (KSV) model of the schizophrenias. Cowen, M.A., Green, M. Schizophr. Res. (1993) [Pubmed]
  7. KAL, a gene mutated in Kallmann's syndrome, is expressed in the first trimester of human development. Duke, V.M., Winyard, P.J., Thorogood, P., Soothill, P., Bouloux, P.M., Woolf, A.S. Mol. Cell. Endocrinol. (1995) [Pubmed]
  8. Kabuki make-up (Niikawa-Kuroki) syndrome: cognitive abilities and autistic features. Ho, H.H., Eaves, L.C. Developmental medicine and child neurology. (1997) [Pubmed]
  9. The psychosocial impact of Klinefelter syndrome--a 10 year review. Simm, P.J., Zacharin, M.R. J. Pediatr. Endocrinol. Metab. (2006) [Pubmed]
  10. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Dodé, C., Levilliers, J., Dupont, J.M., De Paepe, A., Le Dû, N., Soussi-Yanicostas, N., Coimbra, R.S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pêcheux, C., Le Tessier, D., Cruaud, C., Delpech, M., Speleman, F., Vermeulen, S., Amalfitano, A., Bachelot, Y., Bouchard, P., Cabrol, S., Carel, J.C., Delemarre-van de Waal, H., Goulet-Salmon, B., Kottler, M.L., Richard, O., Sanchez-Franco, F., Saura, R., Young, J., Petit, C., Hardelin, J.P. Nat. Genet. (2003) [Pubmed]
  11. Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting. Rugarli, E.I., Lutz, B., Kuratani, S.C., Wawersik, S., Borsani, G., Ballabio, A., Eichele, G. Nat. Genet. (1993) [Pubmed]
  12. Deletions of the steroid sulphatase gene in "classical" X-linked ichthyosis and in X-linked ichthyosis associated with Kallmann syndrome. Ballabio, A., Sebastio, G., Carrozzo, R., Parenti, G., Piccirillo, A., Persico, M.G., Andria, G. Hum. Genet. (1987) [Pubmed]
  13. Kallmann syndrome: MR findings. Knorr, J.R., Ragland, R.L., Brown, R.S., Gelber, N. AJNR. American journal of neuroradiology. (1993) [Pubmed]
  14. Kabuki make-up syndrome associated with chronic idiopathic thrombocytopenic purpura. Watanabe, T., Miyakawa, M., Satoh, M., Abe, T., Oda, Y. Acta paediatrica Japonica; Overseas edition. (1994) [Pubmed]
  15. Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome. Söderlund, D., Canto, P., Méndez, J.P. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  16. Kallmann syndrome: fibroblast growth factor signaling insufficiency? Dodé, C., Hardelin, J.P. J. Mol. Med. (2004) [Pubmed]
  17. Methylation of multiple genes in gastric glands with intestinal metaplasia: a disorder with polyclonal origins. Mihara, M., Yoshida, Y., Tsukamoto, T., Inada, K., Nakanishi, Y., Yagi, Y., Imai, K., Sugimura, T., Tatematsu, M., Ushijima, T. Am. J. Pathol. (2006) [Pubmed]
  18. Coexistence of Kallmann syndrome and complete androgen insensitivity in the same patient. Gannagé-Yared, M.H., Dodé, C., Ghanem, I., Chouery, E., Jalkh, N., Hardelin, J.P., Mégarbané, A. Eur. J. Endocrinol. (2005) [Pubmed]
  19. Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. Pitteloud, N., Acierno, J.S., Meysing, A.U., Dwyer, A.A., Hayes, F.J., Crowley, W.F. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  20. Factors involved in the migration of neuroendocrine hypothalamic neurons. Maggi, R., Cariboni, A., Zaninetti, R., Samara, A., Stossi, F., Pimpinelli, F., Giacobini, P., Consalez, G.G., Rugarli, E., Piva, F. Archives italiennes de biologie. (2005) [Pubmed]
  21. CADA, a novel CD4-targeted HIV inhibitor, is synergistic with various anti-HIV drugs in vitro. Vermeire, K., Princen, K., Hatse, S., De Clercq, E., Dey, K., Bell, T.W., Schols, D. AIDS (2004) [Pubmed]
  22. Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene. Maya-Núñez, G., Cuevas-Covarrubias, S., Zenteno, J.C., Ulloa-Aguirre, A., Kofman-Alfaro, S., Méndez, J.P. Clin. Endocrinol. (Oxf) (1998) [Pubmed]
  23. C. elegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations. Hudson, M.L., Kinnunen, T., Cinar, H.N., Chisholm, A.D. Dev. Biol. (2006) [Pubmed]
  24. New insights in the genetics of isolated hypogonadotropic hypogonadism. Iovane, A., Aumas, C., de Roux, N. Eur. J. Endocrinol. (2004) [Pubmed]
  25. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. Dod??, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.P. PLoS Genet. (2006) [Pubmed]
  26. A yeast artificial chromosome contig linking the steroid sulfatase and Kallmann syndrome loci on the human X chromosome short arm. Lee, W.C., Ferrero, G.B., Chinault, A.C., Yen, P.H., Ballabio, A. Genomics (1993) [Pubmed]
  27. Structure of the X-linked Kallmann syndrome gene and its homologous pseudogene on the Y chromosome. del Castillo, I., Cohen-Salmon, M., Blanchard, S., Lutfalla, G., Petit, C. Nat. Genet. (1992) [Pubmed]
  28. Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hardelin, J.P., Levilliers, J., Blanchard, S., Carel, J.C., Leutenegger, M., Pinard-Bertelletto, J.P., Bouloux, P., Petit, C. Hum. Mol. Genet. (1993) [Pubmed]
  29. Detection of KAL-1 gene deletion with fluorescence in situ hybridization. Hou, J.W., Tsai, W.Y., Wang, T.R. J. Formos. Med. Assoc. (1999) [Pubmed]
  30. An assessment of health hazard/health risk appraisal. Wagner, E.H., Beery, W.L., Schoenbach, V.J., Graham, R.M. American journal of public health. (1982) [Pubmed]
  31. Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome. Hardelin, J.P., Julliard, A.K., Moniot, B., Soussi-Yanicostas, N., Verney, C., Schwanzel-Fukuda, M., Ayer-Le Lievre, C., Petit, C. Dev. Dyn. (1999) [Pubmed]
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