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Proc Natl Acad Sci U S A. Sep 1, 1992; 89(17): 8190–8194.

X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.


Kallmann syndrome represents the association of hypogonadotropic hypogonadism with anosmia. This syndrome is from a defect in the embryonic migratory pathway of gonadotropin-releasing hormone synthesizing neurons and olfactory axons. A candidate gene for the X chromosome-linked form of the syndrome was recently isolated by using a positional cloning strategy based on deletion mapping in the Xp22.3 region. With the PCR, two exons of this candidate gene were amplified on the genomic DNAs from 18 unrelated patients affected with the X chromosome-linked Kallmann syndrome. Three different base transitions--all leading to a stop codon--and one single-base deletion responsible for a frameshift were identified. We thus conclude that the candidate gene is the actual KAL gene responsible for the X chromosome-linked Kallmann syndrome. Furthermore, unilateral renal aplasia in two unrelated patients carrying a stop mutation indicates that the KAL gene is itself responsible for this Kallmann syndrome-associated anomaly. The gene is, therefore, also involved in kidney organogenesis. Additional neurologic symptoms in Kallmann patients are also discussed.

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  • DE MORSIER G. Etudes sur les dysraphies crânio-encéphaliques. I. Agénésie des lobes olfactifs (télencéphaloschizis latéral) et des commissures calleuse et antérieure (télencéphaloschizis médian); la dysplasie olfacto-génitale. Schweiz Arch Neurol Psychiatr. 1954;74(1-2):309–361. [PubMed]
  • Sparkes RS, Simpson RW, Paulsen CA. Familial hypogonadotropic hypogonadism with anosmia. Arch Intern Med. 1968 Jun;121(6):534–538. [PubMed]
  • Santen RJ, Paulsen CA. Hypogonadotropic eunuchoidism. I. Clinical study of the mode of inheritance. J Clin Endocrinol Metab. 1973 Jan;36(1):47–54. [PubMed]
  • White BJ, Rogol AD, Brown KS, Lieblich JM, Rosen SW. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am J Med Genet. 1983 Jul;15(3):417–435. [PubMed]
  • Chaussain JL, Toublanc JE, Feingold J, Naud C, Vassal J, Job JC. Mode of inheritance in familial cases of primary gonadotropic deficiency. Horm Res. 1988;29(5-6):202–206. [PubMed]
  • Jones JR, Kemmann E. Olfacto-genital dysplasia in the female. Obstet Gynecol Annu. 1976;5:443–466. [PubMed]
  • Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell. 1991 Oct 18;67(2):423–435. [PubMed]
  • Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991 Oct 10;353(6344):529–536. [PubMed]
  • Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature. 1989 Mar 9;338(6211):161–164. [PubMed]
  • Wray S, Grant P, Gainer H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8132–8136. [PMC free article] [PubMed]
  • Ronnekleiv OK, Resko JA. Ontogeny of gonadotropin-releasing hormone-containing neurons in early fetal development of rhesus macaques. Endocrinology. 1990 Jan;126(1):498–511. [PubMed]
  • Schwanzel-Fukuda M, Bick D, Pfaff DW. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res. 1989 Dec;6(4):311–326. [PubMed]
  • Schwankhaus JD, Currie J, Jaffe MJ, Rose SR, Sherins RJ. Neurologic findings in men with isolated hypogonadotropic hypogonadism. Neurology. 1989 Feb;39(2 Pt 1):223–226. [PubMed]
  • Kertzman C, Robinson DL, Sherins RJ, Schwankhaus JD, McClurkin JW. Abnormalities in visual spatial attention in men with mirror movements associated with isolated hypogonadotropic hypogonadism. Neurology. 1990 Jul;40(7):1057–1063. [PubMed]
  • Wegenke JD, Uehling DT, Wear JB, Jr, Gordon ES, Bargman JG, Deacon JS, Herrmann JP, Opitz JM. Familial Kallmann syndrome with unilateral renal aplasia. Clin Genet. 1975 May-Jun;7(5):368–381. [PubMed]
  • Breathnach R, Benoist C, O'Hare K, Gannon F, Chambon P. Ovalbumin gene: evidence for a leader sequence in mRNA and DNA sequences at the exon-intron boundaries. Proc Natl Acad Sci U S A. 1978 Oct;75(10):4853–4857. [PMC free article] [PubMed]
  • Senapathy P, Shapiro MB, Harris NL. Splice junctions, branch point sites, and exons: sequence statistics, identification, and applications to genome project. Methods Enzymol. 1990;183:252–278. [PubMed]
  • Petit C, Levilliers J, Weissenbach J. Physical mapping of the human pseudo-autosomal region; comparison with genetic linkage map. EMBO J. 1988 Aug;7(8):2369–2376. [PMC free article] [PubMed]
  • Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. [PMC free article] [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Ballabio A, Sebastio G, Carrozzo R, Parenti G, Piccirillo A, Persico MG, Andria G. Deletions of the steroid sulphatase gene in "classical" X-linked ichthyosis and in X-linked ichthyosis associated with Kallmann syndrome. Hum Genet. 1987 Dec;77(4):338–341. [PubMed]
  • Petit C, Levilliers J, Weissenbach J. Long-range restriction map of the terminal part of the short arm of the human X chromosome. Proc Natl Acad Sci U S A. 1990 May;87(10):3680–3684. [PMC free article] [PubMed]
  • Barker D, Schafer M, White R. Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell. 1984 Jan;36(1):131–138. [PubMed]
  • Nass R. Mirror movement asymmetries in congenital hemiparesis: the inhibition hypothesis revisited. Neurology. 1985 Jul;35(7):1059–1062. [PubMed]
  • Dandekar AM, Robinson EA, Appella E, Qasba PK. Complete sequence analysis of cDNA clones encoding rat whey phosphoprotein: homology to a protease inhibitor. Proc Natl Acad Sci U S A. 1982 Jul;79(13):3987–3991. [PMC free article] [PubMed]
  • Hennighausen LG, Sippel AE. Mouse whey acidic protein is a novel member of the family of 'four-disulfide core' proteins. Nucleic Acids Res. 1982 Apr 24;10(8):2677–2684. [PMC free article] [PubMed]
  • Stetler G, Brewer MT, Thompson RC. Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. Nucleic Acids Res. 1986 Oct 24;14(20):7883–7896. [PMC free article] [PubMed]
  • Seemüller U, Arnhold M, Fritz H, Wiedenmann K, Machleidt W, Heinzel R, Appelhans H, Gassen HG, Lottspeich F. The acid-stable proteinase inhibitor of human mucous secretions (HUSI-I, antileukoprotease). Complete amino acid sequence as revealed by protein and cDNA sequencing and structural homology to whey proteins and Red Sea turtle proteinase inhibitor. FEBS Lett. 1986 Apr 7;199(1):43–48. [PubMed]
  • Wiedow O, Schröder JM, Gregory H, Young JA, Christophers E. Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J Biol Chem. 1990 Sep 5;265(25):14791–14795. [PubMed]
  • Petersen TE, Thøgersen HC, Skorstengaard K, Vibe-Pedersen K, Sahl P, Sottrup-Jensen L, Magnusson S. Partial primary structure of bovine plasma fibronectin: three types of internal homology. Proc Natl Acad Sci U S A. 1983 Jan;80(1):137–141. [PMC free article] [PubMed]
  • Jones FS, Burgoon MP, Hoffman S, Crossin KL, Cunningham BA, Edelman GM. A cDNA clone for cytotactin contains sequences similar to epidermal growth factor-like repeats and segments of fibronectin and fibrinogen. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2186–2190. [PMC free article] [PubMed]
  • Pearson CA, Pearson D, Shibahara S, Hofsteenge J, Chiquet-Ehrismann R. Tenascin: cDNA cloning and induction by TGF-beta. EMBO J. 1988 Oct;7(10):2977–2982. [PMC free article] [PubMed]
  • Just M, Herbst H, Hummel M, Dürkop H, Tripier D, Stein H, Schuppan D. Undulin is a novel member of the fibronectin-tenascin family of extracellular matrix glycoproteins. J Biol Chem. 1991 Sep 15;266(26):17326–17332. [PubMed]
  • Chu ML, Zhang RZ, Pan TC, Stokes D, Conway D, Kuo HJ, Glanville R, Mayer U, Mann K, Deutzmann R, et al. Mosaic structure of globular domains in the human type VI collagen alpha 3 chain: similarity to von Willebrand factor, fibronectin, actin, salivary proteins and aprotinin type protease inhibitors. EMBO J. 1990 Feb;9(2):385–393. [PMC free article] [PubMed]
  • Yamagata M, Yamada KM, Yamada SS, Shinomura T, Tanaka H, Nishida Y, Obara M, Kimata K. The complete primary structure of type XII collagen shows a chimeric molecule with reiterated fibronectin type III motifs, von Willebrand factor A motifs, a domain homologous to a noncollagenous region of type IX collagen, and short collagenous domains with an Arg-Gly-Asp site. J Cell Biol. 1991 Oct;115(1):209–221. [PMC free article] [PubMed]
  • Spring J, Beck K, Chiquet-Ehrismann R. Two contrary functions of tenascin: dissection of the active sites by recombinant tenascin fragments. Cell. 1989 Oct 20;59(2):325–334. [PubMed]
  • Monard D. Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci. 1988 Dec;11(12):541–544. [PubMed]
  • Reichardt LF, Tomaselli KJ. Extracellular matrix molecules and their receptors: functions in neural development. Annu Rev Neurosci. 1991;14:531–570. [PMC free article] [PubMed]
  • Hynes RO, Lander AD. Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell. 1992 Jan 24;68(2):303–322. [PubMed]

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