Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions

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

Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. 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. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome

Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids

Cadherin-23 is a component of early transient lateral links of the auditory sensory cells' hair bundle, the mechanoreceptive structure to sound. This protein also makes up the upper part of the tip links that control gating of the mechanoelectrical transduction channels. We addressed the issue of the molecular complex that anchors these links to the hair bundle F-actin core. By using surface plasmon resonance assays, we show that the cytoplasmic regions of the two cadherin-23 isoforms that do or do not contain the exon68-encoded peptide directly interact with harmonin, a submembrane PDZ (post-synaptic density, disc large, zonula occludens) domain-containing protein, with unusually high affinity. This interaction involves the harmonin Nter-PDZ1 supramodule, but not the C-terminal PDZ-binding motif of cadherin-23. We establish that cadherin-23 directly binds to the tail of myosin VIIa. Moreover, cadherin-23, harmonin and myosin VIIa can form a ternary complex, which suggests that myosin VIIa applies tension forces on hair bundle links. We also show that the cadherin-23 cytoplasmic region, harmonin and myosin VIIa interact with phospholipids on synthetic liposomes. Harmonin and the cytoplasmic region of cadherin-23, both independently and as a binary complex, can bind specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), which may account for the role of this phospholipid in the adaptation of mechanoelectrical transduction in the hair bundle. The distributions of cadherin-23, harmonin, myosin VIIa and PI(4,5)P2 in the growing and mature auditory hair bundles as well as the abnormal locations of harmonin and myosin VIIa in cadherin-23 null mutant mice strongly support the functional relevance of these interactions

Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

<p>Abstract</p> <p>Background</p> <p>Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool.</p> <p>Methods</p> <p>We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3).</p> <p>Results</p> <p>Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel.</p> <p>Conclusions</p> <p>Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.</p

Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells

We assessed the involvement of harmonin-b, a submembranous protein containing PDZ domains, in the mechanoelectrical transduction machinery of inner ear hair cells. Harmonin-b is located in the region of the upper insertion point of the tip link that joins adjacent stereocilia from different rows and that is believed to gate transducer channel(s) located in the region of the tip link's lower insertion point. In Ush1cdfcr-2J/dfcr-2J mutant mice defective for harmonin-b, step deflections of the hair bundle evoked transduction currents with altered speed and extent of adaptation. In utricular hair cells, hair bundle morphology and maximal transduction currents were similar to those observed in wild-type mice, but adaptation was faster and more complete. Cochlear outer hair cells displayed reduced maximal transduction currents, which may be the consequence of moderate structural anomalies of their hair bundles. Their adaptation was slower and displayed a variable extent. The latter was positively correlated with the magnitude of the maximal transduction current, but the cells that showed the largest currents could be either hyperadaptive or hypoadaptive. To interpret our observations, we used a theoretical description of mechanoelectrical transduction based on the gating spring theory and a motor model of adaptation. Simulations could account for the characteristics of transduction currents in wild-type and mutant hair cells, both vestibular and cochlear. They led us to conclude that harmonin-b operates as an intracellular link that limits adaptation and engages adaptation motors, a dual role consistent with the scaffolding property of the protein and its binding to both actin filaments and the tip link component cadherin-23

Avant-propos: Série Maladies chroniques : transition de l’adolescence à l’âge adulte

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Syndrome de Kallmann De Morsier : Insuffisance de signalisation par les FGF ?

Le syndrome de Kallmann De Morsier est une maladie du développement embryonnaire qui associe un hypogonadisme central et une anosmie. Alors que des mutations du gène KAL1 codant pour l’anosmine-1, une protéine présente dans certaines matrices extracellulaires pendant l’organogenèse, avaient été mises en évidence dans la forme liée au chromosome X, des mutations du gène qui code pour FGFR1, l’un des récepteurs des fibroblast growth factors (FGF), ont été récemment identifiées dans une forme autosomique dominante de la maladie. Il reste à découvrir les autres gènes impliqués dans ce syndrome cliniquement et génétiquement hétérogène. Cependant, nous proposons dès à présent une hypothèse physiopathologique unificatrice pour rendre compte de l’aplasie des bulbes olfactifs qui caractérise ce syndrome.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

The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.

International audienceKallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. This failure could be a consequence of the early degeneration of olfactory nerve and terminal nerve fibres, because the latter normally act as guiding cues for the migration of GnRH cells. Defects in GnRH cell fate specification, differentiation, axon elongation or axon targeting to the hypothalamus median eminence may, however, also contribute to GnRH deficiency, at least in some genetic forms of the disease. To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2, and KAL1. Mutations in these genes, however, account for barely 30% of all KS cases. Mutations in FGFR1, encoding fibroblast growth factor receptor 1, underlie an autosomal dominant form of the disease. Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous or compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic or oligogenic KS transmission modes. Finally, KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked form of the disease. It is believed that anosmin-1 acts as an enhancer of FGF signalling and perhaps of prokineticin signalling too

Vers une thérapie génique de certaines surdités congénitales ?

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Déficits auditifs : recherches émergentes et applications chez l'enfant

La déficience auditive est le déficit sensoriel le plus fréquent chez l’enfant.Ses conséquences sur le développement du langage et de la communicationsont importantes.Les surdités peuvent être classées selon le degré de perte auditive (moyennesur les fréquences 500, 1 000, 2 000 et 4 000 Hz de la meilleure oreille) ensurdités légères, moyennes, sévères et profondes. Les surdités sévères et profondescorrespondent à une déficience auditive qui, sans réhabilitation,entraîne l’absence d’acquisition du langage oral. Même les surdités moyennes,qui représentent 50 % des surdités, ont un impact sur les apprentissagesscolaires, le développement cognitif et l’adaptation sociale qui ne doit pasêtre sous-estimée.Les surdités peuvent être également classées selon l’emplacement du défautprimaire (oreille externe, moyenne, interne). À partir de l’audiogrammeobtenu chez l’enfant (comparaison des courbes de conduction aérienne etosseuse), on distingue les surdités de perception (oreille interne, nerf auditif,voies auditives centrales) et les surdités de transmission (oreille moyenneessentiellement).Les surdités de l’enfant peuvent être isolées (non syndromiques) ou syndromiques(c’est-à-dire associées à des anomalies d’autres organes). La prévalencede la surdité augmente avec l’âge. Certains types de surdité, enparticulier les surdités génétiques, apparaissent durant l’enfance ou même àl’âge adulte. La répartition des surdités prélinguales (c’est-à-dire survenantavant l’âge d’apparition du langage) dans les pays développés est aujourd’huiestimée à 10-15 % de surdités syndromiques héréditaires, 60-65 % de surditésisolées héréditaires et 20-25 % de surdités d’autre origine (infections,médicaments, complication de la prématurité…).L’identification des gènes responsables constitue un axe récent de recherchesur l’origine des déficits auditifs. Ces gènes codent pour des protéines quisont impliquées dans les processus cellulaires du fonctionnement de lacochlée, organe de l’audition dans l’oreille interne. Leur connaissance présenteun intérêt pour la pratique clinique quotidienne car elle peut permettrede cibler un diagnostic moléculaire pour le conseil génétique etpronostique.En France, il n’existe pas encore d’organisation générale permettant de réalisersystématiquement le dépistage à la naissance. La rubrique « dépistagenéonatal de la surdité » figure néanmoins dans le carnet de santé depuis 1970. Des outils non invasifs chez le nouveau-né existent depuis quelquesannées (otoémissions acoustiques, potentiels évoqués auditifs automatisés).Si une anomalie est décelée par un test de dépistage en maternité, des testsplus complexes à visée diagnostique doivent être réalisés en milieu spécialisépour évaluer précisément le niveau auditif.Par ailleurs, on sait que la prise en charge doit être précoce afin de se situerpendant la période critique (liée à la plasticité cérébrale), durant laquelle lelangage oral s’organise à partir des sons entendus. Les possibilités de prise encharge évoluent profondément, avec en particulier la réhabilitation des surditésprofondes par implant cochléaire. Toutes ces avancées peuvent contribuerà réduire fortement le handicap lié à cette déficience.De nouveaux défis se posent donc à l’acoustique, discipline déjà ancienne,pour l’amélioration du dépistage, du diagnostic et de la prise en charge qu’ils’agisse d’appareillages prothétiques ou d’implants cochléaires qui présententencore des imperfections multiples dans un environnement bruyant.(...