Rettov syndróm je neurovývinové ochorenie detského veku viazané na chromozóm X, ktoré primárne postihuje dievčatá. Celosvetový výskyt je 1 : 10 000 – 15 000 živonarodených dievčat. Je jednou z hlavných príčin závažnej mentálnej retardácie u dievčat. Klinický obraz tohto syndrómu prvýkrát opísal rakúsky pediater Andreas Rett v roku 1966. Takmer 20 rokov uplynulo, kým bol Rettov syndróm akceptovaný ako špecifická chorobná jednotka. V roku 1999 dokázala Huda Zoghbiová mutáciu v MECP2 géne ako príčinu Rettovho syndrómu. Klinicky sa pri Rettovom syndróme rozlišoval klasický a atypický fenotyp. Klasický Rettov syndróm je charakterizovaný normálnym vývinom od narodenia do 6 mesiacov s následnou regresiou, so stratou dovtedy získaných schopností a reči a s vývojom stereotypných pohybov rúk a veľmi častým vznikom mikrocefálie. Atypické varianty boli rozdelené na kongenitálny variant, variant s včasným začiatkom záchvatov, forme fruste s neskorším nástupom príznakov, variant s regresiou v neskoršom detskom veku a variant so zachovanými rečovými prejavmi. V týchto atypických prípadoch sa mutácie v MECP2 géne dokázali len v 50 – 70 %. Pri atypických formách boli odhalené mutácie v génoch CDKL5 a FOXG1, zvlášť pri variante s včasným začiatkom záchvatov a pri kongenitálnej forme.

Rett syndrome is a X-linked progressive childhood neurodevelopmental disorder that primarily affects females. The incidence is 1 : 10 000 – 15 000 females worldwide, making it one of the major causes of severe mental retardation in females. The clinical characteristics of this syndrome were first reported in the German literature in 1966 by Austrian pediatrician Andreas Rett. Almost 20 years have passed since Rett syndrome became internationally accepted as a unique disorder. The association of Rett syndrome with mutations in the methyl-CpG binding protein 2 gene (MECP2) was recognised in 1999 by Huda Zoghbi. Clinically it can be classified into classic and atypical phenotype. Classic Rett syndrome is characterized by normal development from birth until 6 months of age, followed by regression with loss of acquired skills and speech and development, stereotypic hand movements and frequently development of microcephaly. Several atypical Rett variants have been described that include the congenital variant, the early onset seizure variant, the forme fruste with the late onset of symptoms, the late regression variant, and the variant with spared communication skills. MECP2 gene alterations are present only in 50-70 % atypical cases. Mutations in other genes, most often CDKL5 and FOXG1 have been discovered and associated with atypical Rett variants mostly with early onset seizures and congenital form.

Rettův syndrom (RTT) je vážné X-vázané neurologické onemocnění, postihující především dívky. Patří mezi poruchy autistického spektra a je charakterizován zejména regresem psychomotorického vývoje, ztrátou řeči, mikrocefalií, stereotypními pohyby rukou a záchvaty. Většina případů RTT je způsobena de novo mutacemi v genu pro metyl-CpG-vazebný protein 2 (MECP2) a jen velmi ojediněle se jedná o familiární výskyt. Produkt tohoto genu, MeCP2 protein, sehrává důležitou roli v chromatinové remodelaci, regulaci genové exprese a také se účastní modulace RNA sestřihu. Některé případy atypického RTT mohou být způsobeny mutacemi v dalších genech, např. CDKL5, FOXG1 nebo NTNG1. Tento přehledový článek uvádí souhrn současných poznatků o Rettovu syndromu, klinickém obrazu pacientů v jednotlivých stadiích, molekulární podstatě, diagnostických kritériích, terapeutických přístupech a o možnostech DNA diagnostiky.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder affecting almost exclusively girls. It belongs to the family of autistic spectrum disorders, and it is characterized by psychomotor regression, loss of acquired speech, microcephaly, repetitive stereotypic hand movements, and seizures. Most of RTT cases are caused by de novo mutations in the gene for the methyl-CpG-binding protein 2 (MECP2), and familial cases are extremely rare. The MECP2 gene product plays an important role in chromatin remodeling, regulation of gene expression and is also involved in RNA splicing. Some atypical RTT cases are caused by mutations in other genes, such as CDKL5, FOXG1 or NTNG1. In this paper we give an overview of RTT, its clinical aspects, molecular basis, diagnostic criteria, medical management and DNA diagnosis.

• MeSH
• diagnostické techniky molekulární metody   využití   MeSH
• farmakoterapie metody   využití   MeSH
• financování organizované MeSH
• genetická heterogenita MeSH
• geny vázané na chromozom X genetika   MeSH
• klinický obraz nemoci MeSH
• lidé MeSH
• mentální retardace diagnóza   etiologie   genetika   MeSH
• místa sestřihu RNA genetika   MeSH
• mutace genetika   MeSH
• neurologické manifestace MeSH
• nežádoucí účinky léčiv MeSH
• polymerázová řetězová reakce využití   MeSH
• progrese nemoci MeSH
• protein - isoformy genetika   izolace a purifikace   MeSH
• protein 2 vázající methyl-CpG izolace a purifikace   MeSH
• Rettův syndrom diagnóza   etiologie   terapie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH

SOX2 is essential for maintaining neurosensory stem cell properties, although its involvement in the early neurosensory development of cranial placodes remains unclear. To address this, we used Foxg1-Cre to conditionally delete Sox2 during eye, ear, and olfactory placode development. Foxg1-Cre mediated early deletion of Sox2 eradicates all olfactory placode development, and disrupts retinal development and invagination of the lens placode. In contrast to the lens and olfactory placodes, the ear placode invaginates and delaminates NEUROD1 positive neurons. Furthermore, we show that SOX2 is not necessary for early ear neurogenesis, since the early inner ear ganglion is formed with near normal central projections to the hindbrain and peripheral projections to the undifferentiated sensory epithelia of E11.5-12.5 ears. However, later stages of ear neurosensory development, in particular, the late forming auditory system, critically depend on the presence of SOX2. Our data establish distinct differences for SOX2 requirements among placodal sensory organs with similarities between olfactory and lens but not ear placode development, consistent with the unique neurosensory development and molecular properties of the ear.

• MeSH
• apoptóza MeSH
• myši knockoutované MeSH
• myši MeSH
• neurogeneze * MeSH
• nosní sliznice embryologie   metabolismus   MeSH
• oční čočka embryologie   metabolismus   MeSH
• transkripční faktory SOXB1 genetika   metabolismus   MeSH
• vnitřní ucho cytologie   embryologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

We review the molecular basis of three related basic helix-loop-helix (bHLH) genes (Neurog1, Neurod1, and Atoh1) and upstream regulators Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires early expression of Neurog1, followed by its downstream target Neurod1, which downregulates Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 and Neurog1 expression for various aspects of development. Several experiments show a partial uncoupling of Atoh1/Neurod1 (spiral ganglia and cochlea) and Atoh1/Neurog1/Neurod1 (cochlear nuclei). In this review, we integrate the cellular and molecular mechanisms that regulate the development of auditory system and provide novel insights into the restoration of hearing loss, beyond the limited generation of lost sensory neurons and hair cells.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Fibrotic diseases are a group of pathologies with high incidence and mortality. Despite extensive research efforts, effective therapies are still not available. Understanding the molecular mechanisms driving the onset, progression and possible resolution of fibrosis is a prerequisite to the development of successful therapies. The central role of the TGF-β pathway and myofibroblasts in the pathogenesis of fibrosis is now generally accepted. The possible mechanisms of myofibroblast elimination or dedifferentiation, on the other hand, are still almost uncharted territory. Here we show that sustained expression of some components of MAPK signaling pathway (PDGFB, Ha-Ras(G12V) or the transcription factor EGR4) in primary chicken embryo dermal myofibroblasts results in a loss of autocrine TGF-β signaling and suppression of the myofibroblastic phenotype, characterized by the loss of alpha smooth muscle actin fibers and a substantial reduction in the production of extracellular matrix. Detailed analysis of the possible molecular mechanisms employed by EGR4 revealed FOXG1, BAMBI, NAB1, NAB2 and DUSP5 genes forming an EGR4 regulated network counteracting autocrine TGF-β signaling. We have also found that a combination of chemical inhibition of TGF-β signaling and perturbation of MAPK signaling with phorbol ester mimics the anti-fibrotic effects of PDGFB, Ha-Ras(G12V) and EGR4.

• MeSH
• aktiny genetika   metabolismus   MeSH
• dediferenciace buněk * MeSH
• forbolové estery farmakologie   MeSH
• kuřecí embryo MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• myofibroblasty cytologie   metabolismus   MeSH
• signální transdukce MeSH
• transformující růstový faktor beta metabolismus   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

UNLABELLED: Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastatic-associated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns. IMPLICATIONS: This study provides new mechanistic insight into a HOPX-regulated metastatic dissemination signature.

• MeSH
• buněčný cyklus MeSH
• down regulace MeSH
• experimentální sarkom genetika   patologie   sekundární   MeSH
• forkhead transkripční faktory genetika   metabolismus   MeSH
• genový knockdown MeSH
• geny src MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• kur domácí MeSH
• metastázy nádorů genetika   MeSH
• molekuly buněčné adheze nervové genetika   metabolismus   MeSH
• nádorová transformace buněk genetika   MeSH
• nádorové buněčné linie MeSH
• pohyb buněk MeSH
• ptačí proteiny genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• stanovení celkové genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix-loop-helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons' fate into "hair cells", highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of "intraganglionic" HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

• MeSH
• kochlea cytologie   metabolismus   MeSH
• lidé MeSH
• neurogeneze genetika   fyziologie   MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vláskové buňky metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum. METHODS: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained. RESULTS: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2. CONCLUSIONS: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.

• MeSH
• dítě MeSH
• dystonie genetika   MeSH
• epileptické syndromy komplikace   genetika   MeSH
• fenotyp MeSH
• forkhead transkripční faktory genetika   MeSH
• lidé MeSH
• mladiství MeSH
• nemoci mozku komplikace   genetika   MeSH
• neurovývojové poruchy komplikace   genetika   MeSH
• předškolní dítě MeSH
• protein 2 vázající methyl-CpG genetika   MeSH
• proteiny nervové tkáně genetika   MeSH
• proteiny vázající GTP - alfa-podjednotky Gi-Go genetika   MeSH
• receptory GABA-A genetika   MeSH
• receptory GABA-B genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

In electroreceptive jawed vertebrates, embryonic lateral line placodes give rise to electrosensory ampullary organs as well as mechanosensory neuromasts. Previous reports of shared gene expression suggest that conserved mechanisms underlie electroreceptor and mechanosensory hair cell development and that electroreceptors evolved as a transcriptionally related "sister cell type" to hair cells. We previously identified only one transcription factor gene, Neurod4, as ampullary organ-restricted in the developing lateral line system of a chondrostean ray-finned fish, the Mississippi paddlefish (Polyodon spathula). The other 16 transcription factor genes we previously validated in paddlefish were expressed in both ampullary organs and neuromasts. Here, we used our published lateral line organ-enriched gene-set (arising from differential bulk RNA-seq in late-larval paddlefish), together with a candidate gene approach, to identify 25 transcription factor genes expressed in the developing lateral line system of a more experimentally tractable chondrostean, the sterlet (Acipenser ruthenus, a small sturgeon), and/or that of paddlefish. Thirteen are expressed in both ampullary organs and neuromasts, consistent with conservation of molecular mechanisms. Seven are electrosensory-restricted on the head (Irx5, Irx3, Insm1, Sp5, Satb2, Mafa and Rorc), and five are the first-reported mechanosensory-restricted transcription factor genes (Foxg1, Sox8, Isl1, Hmx2 and Rorb). However, as previously reported, Sox8 is expressed in ampullary organs as well as neuromasts in a catshark (Scyliorhinus canicula), suggesting the existence of lineage-specific differences between cartilaginous and ray-finned fishes. Overall, our results support the hypothesis that ampullary organs and neuromasts develop via largely conserved transcriptional mechanisms, and identify multiple transcription factors potentially involved in the formation of electrosensory versus mechanosensory lateral line organs.

• Publikační typ
• časopisecké články MeSH