[Kallmann De Morsier syndrome: FGF-signaling insufficiency?].
Kallmann syndrome (KAL) associates hypogonadotropic hypogonadism and anosmia, i.e. a deficiency of the sense of smell. Anosmia is related to the absence or the hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency, and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. Kallmann syndrome is genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease, KAL-1, has been identified in 1991. KAL1 encodes a ~95 kDa glycoprotein of unknown function, which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL-2), combined to the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF-signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of the KAL1 gene product, the extracellular matrix protein anosmin-1, is to enhance FGF-signaling, and suggest that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.
Dodé
Catherine
C
Institut Cochin et Laboratoire de Biochimie et génétique moléculaire, Hôpital Cochin, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
Hardelin
Jean-Pierre
JP
D035843:Biomedical Research; D002648:Child; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006801:Humans; D017436:Kallmann Syndrome / Q000209:etiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D015398:Signal Transduction
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D005346:Fibroblast Growth Factors