Convergent pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201401 | GEO | 2022/07/27
REPOSITORIES: GEO
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Project description:Kallmann Syndrome (KS) is a rare human genetic disorder characterized by the hypogonadotropic hypogonadism with the reduction or absence of olfactory sense. The mutations on the multiple genes including Chemokine Prokineticin-2 (PROK2) were considered to contribute to the abnormal migration of gonadotropin-releasing hormone (GnRH) neurons in embryonic stage. Here, we submit RNA-seq of the peripheral blood and the cell free miRNA-seq in the serum of one family, in which the KS patient has the same mutation of PROK2 (c.223-4C>A) with his mother, and the genetic phenotype of his father is normal. The sexual development and function of his parents are normal.
2020-05-01 | E-MTAB-8919 | biostudies-arrayexpress
Project description:Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in >34 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause the same outcome of KS are not fully understood. Here we show that disruptions of KS-linked genes affect the same biological processes, indicating convergent molecular mechanisms underlying KS. We carried out machine learning-based predictions and found that KS-linked mutations in heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) are likely loss-of-function mutations. We next disrupted Hs6st1 and another KS-linked gene, fibroblast growth factor receptor 1 (Fgfr1), in mouse neuronal cells and measured transcriptome changes using RNA sequencing. We found that disruptions of Hs6st1 and Fgfr1 altered genes in the same biological processes, including the upregulation of genes in extracellular pathways and the downregulation of genes in chromatin pathways. Moreover, we performed genomics and bioinformatics analyses and found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS. Together, our results demonstrate how different KS-linked genes work coordinately in a convergent signaling pathway to regulate the same biological processes, thus providing new insights into KS.
| S-EPMC9759331 | biostudies-literature
Project description:The olfactory sensory system is formed by the coordinated morphogenesis and differentiation of the peripheral olfactory epithelium (OE) and the anterior forebrain. At early stages, immature olfactory receptor neurons (ORN) elongate their axons to penetrate the brain basement membrane, contact and form synapses with projection neurons of the olfactory bulb primordium. Axonal elongation is accompanied by migration of the GnRH+ neurons, followed by their ingression in the septo-hypothalamic area of the forebrain. This process is specifically impaired in the KallmannM-bM-^@M-^Ys syndrome (KS), a disorder characterized by anosmia and central hypogonadism. A set of transcription factors are master regulators of olfactory connectivity and GnRH neuron migration. We explored the transcriptional network underlying this process, by profiling the OE and adjacent mesenchyme at distinct embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene essential for olfactory development, that causes a KS-like phenotype when deleted. We also applied analysis of conserved co-expression to integrate the obtained data with information on KS disease genes. The prevalent categories of genes differentially expressed during development are neuronal differentiation, extracellular remodelling and cell adhesion. From the analysis of Dlx5 mutant tissues we identify about 120 genes with a prevalence of intermediate filaments, cell signalling, epithelial and neuronal differentiation. Filtering for true OE expression and for the presence of Dlx5 binding sites, yielded twenty genes, of the following categories: 1) transmembrane adhesion/receptor molecules, 2) axon-glia interaction molecules, 3) synaptic proteins, 4) scaffold/adapter for signalling molecules. To functionally analyze these genes in vivo, we used three zebrafish fluorescent reporter zebrafish strains, in which we monitored early phases of olfactory/GnRH development upon gene downmodulation. The depletion of three (of five) Dlx5 targets affected axonal extension and targeting, while two (of two) altered GnRH neuron position and neurite organization. In one experiment we compare the olfactrory sensory epithelium from wild-type embryos, at three times of development, i.e. E11.5, E12.5 and E14.5. In a second experiment we compare the olfactory sensory epithelium from wild-type embryo with that from Dlx5 knock-out embryos, at the age E12.5
2014-01-31 | E-GEOD-52800 | biostudies-arrayexpress
Project description:The olfactory sensory system is formed by the coordinated morphogenesis and differentiation of the peripheral olfactory epithelium (OE) and the anterior forebrain. At early stages, immature olfactory receptor neurons (ORN) elongate their axons to penetrate the brain basement membrane, contact and form synapses with projection neurons of the olfactory bulb primordium. Axonal elongation is accompanied by migration of the GnRH+ neurons, followed by their ingression in the septo-hypothalamic area of the forebrain. This process is specifically impaired in the Kallmann’s syndrome (KS), a disorder characterized by anosmia and central hypogonadism. A set of transcription factors are master regulators of olfactory connectivity and GnRH neuron migration. We explored the transcriptional network underlying this process, by profiling the OE and adjacent mesenchyme at distinct embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene essential for olfactory development, that causes a KS-like phenotype when deleted. We also applied analysis of conserved co-expression to integrate the obtained data with information on KS disease genes. The prevalent categories of genes differentially expressed during development are neuronal differentiation, extracellular remodelling and cell adhesion. From the analysis of Dlx5 mutant tissues we identify about 120 genes with a prevalence of intermediate filaments, cell signalling, epithelial and neuronal differentiation. Filtering for true OE expression and for the presence of Dlx5 binding sites, yielded twenty genes, of the following categories: 1) transmembrane adhesion/receptor molecules, 2) axon-glia interaction molecules, 3) synaptic proteins, 4) scaffold/adapter for signalling molecules. To functionally analyze these genes in vivo, we used three zebrafish fluorescent reporter zebrafish strains, in which we monitored early phases of olfactory/GnRH development upon gene downmodulation. The depletion of three (of five) Dlx5 targets affected axonal extension and targeting, while two (of two) altered GnRH neuron position and neurite organization.
2014-01-31 | GSE52800 | GEO
Project description:In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. The KS patients display a diverse adult phenotype with increased height, gynaecomastia, and hypergonadotropic hypogonadism as the most common symptoms. Men with KS are almost always infertile due to testicular degeneration, which accelerates during puberty. Very few studies investigated the global gene expression analysis of adult KS testes and, more importantly, which cell types the differentially expressed transcripts originate from. Transcriptome analysis by RNA sequencing of fixed and paraffin embedded testes originating from 3 adult KS samples and 3 adult cellularity-matched controls revealed 236 differentially expressed transcripts in the adult KS testis. To examine the cellular origin of the differentially expressed transcripts, transcriptome profiling was also carried out on 4 testes with Sertoli Cell-Only and 4 testes with full spermatogenesis. Also, pre-pubertal KS and controls were RNA-sequenced.
2018-05-30 | GSE103905 | GEO
Project description:The pathophysiology of post-infectious and idiopathic olfactory loss is still poorly delineated. Since proteins are key players in olfaction and technical advances including LC-MS/MS mass spectrometry give us the opportunity for detailed analysis of the nasal mucus proteome we aimed to undertake a comparative analysis of the olfactory cleft mucus proteome using mucus samples of the olfactory cleft in patients with idiopathic and postinfectious olfactory disorders versus healthy controls. The study was conceived as a pilot study and included 7 patients with idiopathic hyp- and anosmia, 7 patients with postinfectious hyp- and anosmia and 7 healthy controls. In total, 1117 different proteins were detected in at least 5 patients in at least one group. No significant different overall protein concentrations in patients compared to healthy controls (0.4614 µg/µL, SD=0.26273 vs. 0.5143 µg/µL, SD=3087; p=0.689) were found. Significant correlation regarding olfactory test results (TDI score) and protein concentrations (r=0.114, p=0.623) were either found. Results of this study did not show significant differences regarding the proteomic composition of the olfactory cleft mucus between patients suffering from postinfectious and idiopathic dysosmia versus healthy controls. Thus, central olfactory processing pathways may play a role in idiopathic and postinfectious olfactory disorders.
2018-12-10 | PXD009172 | Pride
Project description:During embryonic development, the olfactory placode (OP) gives rise to various populations of neurons; these include putative olfactory pioneer neurons, different neurons of unknown identity and function, cells of the terminal nerve, and the Gonadotropin-releasing hormone-1 (GnRH-1) neurons. In mice, the GnRH-1 neurons are first detectable in the developing olfactory system around mid-gestation. From here, the GnRH-1 neurons migrate, along the axons of the terminal nerve (TN), to various regions of the developing brain. Once in the brain, the GnRH-1 neurons play a central role in controlling the hypothalamic-pituitary-gonadal (HPG) axis. Early migratory neurons forming from the olfactory placode have been proposed to play a vital role in inducing olfactory bulb morphogenesis. Kallmann syndrome is a condition characterized by defective development of the olfactory system and infertility. Murine studies have demonstrated the critical role of the Prokineticin 2-Prokinteicin Receptor 2 pathway in olfactory bulb morphogenesis and GnRH-1 neuronal migration. Loss-of-function Prokr2 mutations cause both Kallmann syndrome associated with bulb agenesis and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Following Prokr2 expression and lineage tracing, we found that Prokr2 is not expressed by the cells of the developing olfactory bulb but by migratory putative pioneer/terminal nerve neurons. Performing single-cell-RNA-sequencing, we identified genes enriched in the migratory cells of the putative terminal nerve. By integrating genetic lineage tracing and single-cell transcriptomics, we identified previously undescribed populations of migratory neurons that appear to be enriched in the expression of several genes related to olfactory defects, GnRH migratory deficiencies and infertility.
2024-03-11 | GSE234871 | GEO
Project description:Patients with Klinefelter Syndrome have the karyotype 47,XXY. These men are suffering from hypergonadotropic hypogonadism and are infertile. It is debated whether the different hormonal constitution observed in these patients or different gene expression With the Microarray analysis we could identify genes on the X-chromosomes that are upregulated in KS-patietns compared to healthy male controls. But also autosomal genes were found to be differentially regulated.
2015-01-07 | GSE42331 | GEO
Project description:In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. The KS patients display a diverse adult phenotype with increased height, gynaecomastia, and hypergonadotropic hypogonadism as the most common symptoms. Men with KS are almost always infertile due to testicular degeneration, which accelerates during puberty. Very few studies investigated when the germ cell loss begins and whether it is caused by dysgenetic fetal development of the testes. We investigated a series of fetal KS testis tissue samples and found a marked reduction in MAGE-A4-positive pre-spermatogonia in the developing KS gonads compared to controls, indicating a failure of the gonocytes to differentiate into pre-spermatogonia. Transcriptome analysis by RNA sequencing of formalin-fixed and paraffin embedded gonads originating from 4 fetal KS samples and 5 age- and cellularity-matched controls revealed 211 differentially expressed transcripts in the fetal KS testis. We found a significant enrichment of upregulated X-chromosomal transcripts and validated the expression of the pseudoautosomal region 1 (PAR1) gene, AKAP17A. Moreover, we found enrichment of long non-coding RNAs in the KS testes (e.g. LINC01569 and RP11-485F13.1). In conclusion, our data indicates that the testicular phenotype observed among adult men with KS is initiated already in fetal life by failure of the gonocyte differentiation into pre-spermatogonia, which could be due to aberrant expression of long non-coding RNAs.
2018-08-28 | GSE103613 | GEO
Project description:Convergent pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1
| PRJNA831449 | ENA