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Byline: Catherine Dode (1), Jean-Pierre Hardelin (2) Keywords: Kallmann syndrome; Anosmin-1; Fibroblast growth factor receptors Abstract: Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or 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. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approx. 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 (KAL2), combined with 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 anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males. Author Affiliation: (1) Institut Cochin et Laboratoire de Biochimie et Genetique Moleculaire, Hopital Cochin, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France (2) Unite de Genetique des Deficits Sensoriels, INSERM U587, Institut Pasteur, 25 rue du Docteur Roux, 75724, Paris cedex 15, France Article History: Registration Date: 07/06/2004 Received Date: 15/01/2004 Accepted Date: 12/05/2004 Online Date: 08/09/2004

Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total ([Clrn1.sup.ex4-/-]) and postnatal hair cell- specific conditional ([Clrn1.sup.ex4fl/fl] [Myo15-Cre.sup.+/-) knockout mice. [Clrn1.sup.ex4-/-] mice were profoundly deaf, whereas [Clrn1.sup.ex4fl/fl] [Myo15-Cre.sup.+/-] mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and [Ca.sub.V]1.3 [Ca.sup.2+] channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic [Ca.sub.V]1.3 [Ca.sup.2+] channel complex via the [Ca.sub.V][[beta].sub.2] auxiliary subunit and the PDZ domain-containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus-mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in [Clrn1.sup.ex4fl/fl] [Myo15-Cre.sup.+/-] mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients., Introduction Usher syndrome type IIIA (USH3A), characterized by progressive hearing loss and retinitis pigmentosa, is caused by mutations in CLRN1 encoding clarin-1 (refs. 1, 2, and Figure 1A). CLRN1 transcripts [...]

Patients with Kallmann syndrome (KS) have hypogonadotropic hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) and a defective sense of smell related to olfactory bulb aplasia. Based on the findings in a fetus affected by the X chromosome-linked form of the disease, it has been suggested that hypogonadism in KS results from the failed embryonic migration of neuroendocrine GnRH1 cells from the nasal epithelium to the forebrain. We asked whether this singular observation might extend to other developmental disorders that also include arrhinencephaly. We therefore studied the location of GnRH1 cells in fetuses affected by different arrhinencephalic disorders, specifically X-linked KS, CHARGE syndrome, trisomy 13, and trisomy 18, using immunohistochemistry. Few or no neuroendocrine GnRH1 cells were detected in the preoptic and hypothalamic regions of all arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. In all arrhinencephalic fetuses, many GnRH1 cells were present in the frontonasal region, the first part of their migratory path, as were interrupted olfactory nerve fibers that formed bilateral neuromas. Our findings define a pathological sequence whereby a lack of migration of neuroendocrine GnRH cells stems from the primary embryonic failure of peripheral olfactory structures. This can occur either alone, as in isolated KS, or as part of a pleiotropic disease, such as CHARGE syndrome, trisomy 13, and trisomy 18., Introduction Gonadotropin-releasing hormone (GnRH) controls the pttuitarygonadal axis (1). Embrvological studies in various vertebrate species have shown that neuroendocrine GnRH cells (i.e., GnRH1-synthesizing neurons) migrate from the medial part of [...]

Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions (1). These distortions reflect nonlinear [...]