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1.
Exp Eye Res ; 246: 110015, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39089568

RESUMO

Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability, is a monogenic neurodevelopmental disorder caused by a loss-of-function mutation of the FMR1 gene. FMR1 is encoding the Fragile X Messenger Ribonucleo Protein (FMRP) an RNA-binding protein that regulates the translation of synaptic proteins. The absence of FMRP expression has many important consequences on synaptic plasticity and function, leading to the FXS clinical phenotype. Over the last decade, a visual neurosensorial phenotype had been described in the FXS patients as well as in the murine model (Fmr1-/ymice), characterized by retinal deficits associated to retinal perception alterations. However, although the transcriptomic profile in the absence of FMRP has been studied in the cerebral part of the central nervous system (CNS), there are no actual data for the retina which is an extension of the CNS. Herein, we investigate the transcriptomic profile of mRNA from whole retinas of Fmr1-/ymice. Interestingly, we found a specific signature of Fmrp absence on retinal mRNA expression with few common genes compared to other brain studies. Gene Ontology on these retinal specific genes demonstrated an enrichment in retinal development genes as well as in synaptic genes. These alterations could be linked to the reported retinal phenotype of the FXS condition. In conclusion, we describe for the first time, retinal-specific transcriptomic changes in the absence of FMRP.


Assuntos
Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Retina , Transcriptoma , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Animais , Camundongos , Retina/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica , Camundongos Knockout , Regulação da Expressão Gênica/fisiologia , Masculino
2.
Exp Eye Res ; 245: 109964, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38851478

RESUMO

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, few data evaluating the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina are available. Only one in-vivo preclinical study demonstrated that dietary supplementation (DS) prevents the retina from light-induced retinal degeneration; and only one in-vitro study on Müller cells culture showed that glutamate metabolism cycle was key in oxidative stress response. Therefore, we raised the question about the in-vivo effect of DS on glutamate metabolism in the retina. Herein, we showed that the dietary supplementation promotes in-vivo increase of retinal glutamine amount through a higher glutamine synthesis as observed in-vitro on Muller cells. Therefore, we can suggest that the promotion of glutamine synthesis is part of the protective effect of DS against retinal degeneration, acting as a preconditioning mechanism against retinal degeneration.


Assuntos
Antioxidantes , Suplementos Nutricionais , Ácidos Graxos Ômega-3 , Glutamina , Retina , Degeneração Retiniana , Glutamina/metabolismo , Animais , Antioxidantes/farmacologia , Ácidos Graxos Ômega-3/administração & dosagem , Degeneração Retiniana/metabolismo , Degeneração Retiniana/prevenção & controle , Retina/metabolismo , Retina/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Células Cultivadas , Células Ependimogliais/metabolismo , Células Ependimogliais/efeitos dos fármacos , Masculino , Ratos , Modelos Animais de Doenças
3.
Nat Commun ; 15(1): 3583, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38678030

RESUMO

Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.1 expression and function in astrocytes. Further, we reveal that Kir4.1 mRNA is a binding target of FMRP. Finally, we show that the deficit in astroglial Kir4.1 underlies neuronal hyperexcitability and several behavioral defects in Fmr1 knockout mice. Viral delivery of Kir4.1 channels specifically to hippocampal astrocytes from Fmr1 knockout mice indeed rescues normal astrocyte potassium uptake, neuronal excitability, and cognitive and social performance. Our findings uncover an important role for astrocyte dysfunction in the pathophysiology of FXS, and identify Kir4.1 channel as a potential therapeutic target for FXS.


Assuntos
Astrócitos , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Neurônios , Canais de Potássio Corretores do Fluxo de Internalização , Animais , Masculino , Camundongos , Astrócitos/metabolismo , Comportamento Animal , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologia , Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética
4.
Exp Eye Res ; 224: 109238, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36067823

RESUMO

FMRP, the fragile X mental retardation protein coded by the FMR1 gene, is an RNA-binding protein that assists transport, stabilization and translational regulation of specific synaptic mRNAs. Its expression has been found in multiple cell types of central nervous system (CNS) including glial cells where its involvement in glutamate neurotransmitter homeostasis have been shown. Indeed, glutamate homeostasis deficit has been observed in absence of FMRP in-vivo in cortex and hippocampus structures as well as in vitro on astroglial cell culture. Interestingly, the retina which is an extension of the CNS is presenting electrophysiological alterations in absence of FMRP in both human and murine models suggesting neurotransmitter impairments. Therefore, we investigate the consequences of Fmrp absence on Glutamate-Glutamine cycle in whole retinas and primary retinal Müller cells culture which are the main glial cells of the retina. Using the Fmr1-/y mice, we have shown in vivo and in vitro that the absence of Fmrp in Müller cells is characterized by loss of Glutamate-Glutamine cycle homeostasis due to a lower Glutamine Synthetase protein expression and activity. The lack of Fmrp in the retina induces a reduced flow of glutamine synthesis. Our data established for the first time in literature a direct link between the lack of Fmrp and neurotransmitter homeostasis in the retina.


Assuntos
Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Camundongos , Animais , Humanos , Proteína do X Frágil da Deficiência Intelectual/genética , Glutamina , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Glutamato-Amônia Ligase/metabolismo , Retina/metabolismo , Fenótipo , Glutamatos/genética , Camundongos Knockout
5.
J Med Case Rep ; 16(1): 180, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35509069

RESUMO

BACKGROUND: Mutations in the genes encoding the large-conductance calcium-activated potassium channel, especially KCNMA1 encoding its α-subunit, have been linked to several neurological features, including intellectual disability or autism. Associated with neurodevelopmental phenotypes, sensory function disturbances are considered to be important clinical features contributing to a variety of behavioral impairments. Large-conductance calcium-activated potassium channels are important in regulating neurotransmission in sensory circuits, including visual pathways. Deficits in visual function can contribute substantially to poor quality of life, while therapeutic approaches aimed at addressing such visual deficits represent opportunities to improve neurocognitive and neurobehavioral outcomes. CASE PRESENTATION: We describe the case of a 25-year-old Caucasian male with autism spectrum disorder and severe intellectual disability presenting large-conductance calcium-activated potassium channel haploinsufficiency due to a de novo balanced translocation (46, XY, t [9; 10] [q23;q22]) disrupting the KCNMA1 gene. The visual processing pathway of the subject was evaluated using both electroretinography and visual contrast sensitivity, indicating that both retinal bipolar cell function and contrast discrimination performance were reduced by approximately 60% compared with normative control values. These findings imply a direct link between KCNMA1 gene disruption and visual dysfunction in humans. In addition, the subject reported photophobia but did not exhibit strabismus, nystagmus, or other visual findings on physical examination. CONCLUSIONS: This case study of a subject with large-conductance calcium-activated potassium channel haploinsufficiency and photophobia revealed a visual pathway deficit at least at the retinal level, with diminished retinal light capture likely due to bipolar cell dysfunction and an associated loss of contrast sensitivity. The data suggest that large-conductance calcium-activated potassium channels play an important role in the normal functioning of the visual pathway in humans, and that their disruption may play a role in visual and other sensory system symptomatology in large-conductance calcium-activated potassium channelopathies or conditions where disruption of large-conductance calcium-activated potassium channel function is a relevant feature of the pathophysiology, such as fragile X syndrome. This work suggests that the combined use of physiological (electroretinography) and functional (contrast sensitivity) approaches may have utility as a biomarker strategy for identifying and characterizing visual processing deficits in individuals with large-conductance calcium-activated potassium channelopathy. Trial registration ID-RCB number 2019-A01015-52, registered 17/05/2019.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Cálcio , Haploinsuficiência , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Masculino , Fotofobia , Potássio , Qualidade de Vida , Órgãos dos Sentidos
6.
Cell Death Dis ; 13(3): 269, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35338116

RESUMO

Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. However, activation of the STING pathway by airway silica or smoke exposure leads to cell death, self-dsDNA release, and STING/type I IFN dependent acute lung inflammation/ARDS. The inflammatory response induced by a synthetic non-nucleotide-based diABZI STING agonist, in comparison to the natural cyclic dinucleotide cGAMP, is unknown. A low dose of diABZI (1 µg by endotracheal route for 3 consecutive days) triggered an acute neutrophilic inflammation, disruption of the respiratory barrier, DNA release with NET formation, PANoptosis cell death, and inflammatory cytokines with type I IFN dependent acute lung inflammation. Downstream upregulation of DNA sensors including cGAS, DDX41, IFI204, as well as NLRP3 and AIM2 inflammasomes, suggested a secondary inflammatory response to dsDNA as a danger signal. DNase I treatment, inhibition of NET formation together with an investigation in gene-deficient mice highlighted extracellular DNA and TLR9, but not cGAS, as central to diABZI-induced neutrophilic response. Therefore, activation of acute cell death with DNA release may lead to ARDS which may be modeled by diABZI. These results show that airway targeting by STING activator as a therapeutic strategy for infection may enhance lung inflammation with severe ARDS. STING agonist diABZI induces neutrophilic lung inflammation and PANoptosis A, Airway STING priming induce a neutrophilic lung inflammation with epithelial barrier damage, double-stranded DNA release in the bronchoalvelolar space, cell death, NETosis and type I interferon release. B, 1. The diamidobenzimidazole (diABZI), a STING agonist is internalized into the cytoplasm through unknown receptor and induce the activation and dimerization of STING followed by TBK1/IRF3 phosporylation leading to type I IFN response. STING activation also leads to NF-kB activation and the production of pro-inflammatory cytokines TNFα and IL-6. 2. The activation of TNFR1 and IFNAR1 signaling pathway results in ZBP1 and RIPK3/ASC/CASP8 activation leading to MLKL phosphorylation and necroptosis induction. 3. This can also leads to Caspase-3 cleavage and apoptosis induction. 4. Self-dsDNA or mtDNA sensing by NLRP3 or AIM2 induces inflammsome formation leading to Gasdermin D cleavage enabling Gasdermin D pore formation and the release mature IL-1ß and pyroptosis. NLRP3 inflammasome formation can be enhanced by the ZBP1/RIPK3/CASP8 complex. 5. A second signal of STING activation with diABZI induces cell death and the release of self-DNA which is sensed by cGAS and form 2'3'-cGAMP leading to STING hyper activation, the amplification of TBK1/IRF3 and NF-kB pathway and the subsequent production of IFN-I and inflammatory TNFα and IL-6. This also leads to IFI204 and DDX41 upregulation thus, amplifying the inflammatory loop. The upregulation of apoptosis, pyroptosis and necroptosis is indicative of STING-dependent PANoptosis.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Animais , Citocinas/metabolismo , DNA , Inflamassomos/metabolismo , Interleucina-6/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Proteínas de Ligação a RNA , Síndrome do Desconforto Respiratório/genética , SARS-CoV-2 , Fator de Necrose Tumoral alfa/metabolismo
7.
J Neurodev Disord ; 13(1): 45, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625026

RESUMO

BACKGROUND: Disturbances in sensory function are an important clinical feature of neurodevelopmental disorders such as fragile X syndrome (FXS). Evidence also directly connects sensory abnormalities with the clinical expression of behavioral impairments in individuals with FXS; thus, positioning sensory function as a potential clinical target for the development of new therapeutics. Using electroretinography (ERG) and contrast sensitivity (CS), we previously reported the presence of sensory deficits in the visual system of the Fmr1-/y genetic mouse model of FXS. The goals of the current study were two-folds: (1) to assess the feasibility of measuring ERG and CS as a biomarker of sensory deficits in individuals with FXS, and (2) to investigate whether the deficits revealed by ERG and CS in Fmr1-/y mice translate to humans with FXS. METHODS: Both ERG and CS were measured in a cohort of male individuals with FXS (n = 20, 18-45 years) and age-matched healthy controls (n = 20, 18-45 years). Under light-adapted conditions, and using both single flash and flicker (repeated train of flashes) stimulation protocols, retinal function was recorded from individual subjects using a portable, handheld, full-field flash ERG device (RETeval®, LKC Technologies Inc., Gaithersburg, MD, USA). CS was assessed in each subject using the LEA SYMBOLS® low-contrast test (Good-Lite, Elgin, IL, USA). RESULTS: Data recording was successfully completed for ERG and assessment of CS in most individuals from both cohorts demonstrating the feasibility of these methods for use in the FXS population. Similar to previously reported findings from the Fmr1-/y genetic mouse model, individuals with FXS were found to exhibit reduced b-wave and flicker amplitude in ERG and an impaired ability to discriminate contrasts compared to healthy controls. CONCLUSIONS: This study demonstrates the feasibility of using ERG and CS for assessing visual deficits in FXS and establishes the translational validity of the Fmr1-/y mice phenotype to individuals with FXS. By including electrophysiological and functional readouts, the results of this study suggest the utility of both ERG and CS (ERG-CS) as complementary translational biomarkers for characterizing sensory abnormalities found in FXS, with potential applications to the clinical development of novel therapeutics that target sensory function abnormalities to treat core symptomatology in FXS. TRIAL REGISTRATION: ID-RCB number 2019-A01015-52 registered on the 17 May 2019.


Assuntos
Síndrome do Cromossomo X Frágil , Animais , Biomarcadores , Sensibilidades de Contraste , Eletrorretinografia , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Masculino , Camundongos
8.
Nutrients ; 13(9)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34579093

RESUMO

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.


Assuntos
Antioxidantes/farmacologia , Células Ependimogliais/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Glutamina/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultura/farmacologia , Células Ependimogliais/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Camundongos
9.
J Neuroinflammation ; 17(1): 268, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917228

RESUMO

BACKGROUND: Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms. METHODS: We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αß deficient mice. Chronic minocycline administration was performed and cognitive functions were examined trough spatial habituation test. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and fluorescence-activated cell sorting (FACS). RESULTS: We showed that IL-33 administration in mice led to a spatial memory performance defect associated with an increase of inflammatory markers in the hippocampus while minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ demonstrated an increase of proximal intersections per radius in each part of the hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting analysis on isolated microglia, revealed overexpression of IL-1ß, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1αß deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection. CONCLUSION: Thus, hippocampal IL-33 induced an inflammatory state, including IL-1ß overexpression by microglia cells, being causative of the cognitive impairment. These results highlight the pathological role for IL-33 in the central nervous system, independently of a specific neuropathological model.


Assuntos
Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Interleucina-33/farmacologia , Animais , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Inflamação/complicações , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Minociclina/farmacologia , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
10.
F1000Res ; 9: 1482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-35528205

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been a global public health concern. Co-infection of SARS-CoV-2 and other respiratory syndrome has been rarely reported. We report coinfection of SARS-CoV-2 and 2009 H1N1 Influenza strain in a French patient with pneumonia leading to acute respiratory distress syndrome.  The patient also had a medical history of pulmonary sarcoidosis with a restrictive ventilatory syndrome, which would be a supplementary risk to develop a poor outcomes. This case highlights the possible coinfection of two severe SARS-CoV-2 and influenza H1N1 viruses, which presents a higher risk to extend the care duration. The overlapping clinical features of the two respiratory syndromes is a challenge, and awareness is required to recommend an early differential diagnosis.


Assuntos
COVID-19 , Coinfecção , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Síndrome do Desconforto Respiratório , Sarcoidose Pulmonar , COVID-19/complicações , Humanos , Influenza Humana/complicações , Influenza Humana/diagnóstico , Síndrome do Desconforto Respiratório/complicações , SARS-CoV-2
11.
Front Behav Neurosci ; 13: 228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680892

RESUMO

Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability (ID) associated with autistic-like behaviors, is characterized by dys-sensitivity to sensory stimuli, especially vision. In the absence of Fragile Mental Retardation Protein (FMRP), both retinal and cerebral structures of the visual pathway are impaired, suggesting that perception and integration of visual stimuli are altered. However, behavioral consequences of these defects remain unknown. In this study, we used male Fmr1 -/y mice to further define visual disturbances from a behavioral perspective by focusing on three traits characterizing visual modality: perception of depth, contrasts and movements. We performed specific tests (Optomotor Drum, Visual Cliff) to evaluate these visual modalities, their evolution from youth to adulthood, and to assess their involvement in a cognitive task. We show that Fmr1 -/y mice exhibit alteration in their visual skills, displaying impaired perspective perception, a drop in their ability to understand a moving contrasted pattern, and a defect in contrasts discrimination. Interestingly, Fmr1 -/y phenotypes remain stable over time from adolescence to late adulthood. Besides, we report that color and shape are meaningful for the achievement of a cognitive test involving object recognition. Altogether, these results underline the significance of visual behavior alterations in FXS conditions and relevance of assessing visual skills in neuropsychiatric models before performing behavioral tasks, such as cognitive assessments, that involve visual discrimination.

12.
Front Cell Neurosci ; 12: 96, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29681800

RESUMO

Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1-/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO) is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1-/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1-/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions.

13.
Hum Mol Genet ; 26(2): 367-382, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28365779

RESUMO

The cellular and molecular mechanisms underlying neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The ability to generate patient-specific induced pluripotent stem cells (iPSCs) now offers a novel strategy for modelling human diseases. Recent studies have reported the derivation of iPSCs from patients with neurological disorders. The key challenge remains the demonstration of disease-related phenotypes and the ability to model the disease. Here we report a case study with signs of neurodevelopmental disorders (NDDs) harbouring chromosomal rearrangements that were sequenced using long-insert DNA paired-end tag (DNA-PET) sequencing approach. We identified the disruption of a specific gene, GTDC1. By deriving iPSCs from this patient and differentiating them into neural progenitor cells (NPCs) and neurons we dissected the disease process at the cellular level and observed defects in both NPCs and neuronal cells. We also showed that disruption of GTDC1 expression in wild type human NPCs and neurons showed a similar phenotype as patient's iPSCs. Finally, we utilized a zebrafish model to demonstrate a role for GTDC1 in the development of the central nervous system. Our findings highlight the importance of combining sequencing technologies with the iPSC technology for NDDs modelling that could be applied for personalized medicine.


Assuntos
Transtorno do Espectro Autista/genética , Glicosiltransferases/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Diferenciação Celular/genética , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Genoma Humano , Glicosiltransferases/biossíntese , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Medicina de Precisão , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
14.
Am J Med Genet A ; 170(7): 1806-12, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27113058

RESUMO

Terminal deletion of the long arm of the chromosome 10 is a rare but well known abnormality, with a large phenotypic variability. Very few data are available about subtelomeric deletion 10q26 patients without intellectual disability. Herein, we report the case of a young adult with a classical 10q26.2qter deletion. She exhibited mainly short stature at birth and in childhood/adulthood without intellectual disability or behavioral problems. After clinical and neuropsychological assessments, we performed genomic array and transcriptomic analysis and compared our results to the data available in the literature. The patient presents a 6.525 Mb heterozygous 10q26.2qter deletion, encompassed 48 genes. Among those genes, DOCK1, C10orf90, and CALY previously described as potential candidate genes for intellectual disability, were partially or completed deleted. Interestingly, they were not deregulated as demonstrated by transcriptomic analysis. This allowed us to suggest that the mechanism involved in the deletion 10qter phenotype is much more complex that only the haploinsufficiency of DOCK1 or other genes encompassed in the deletion. Genomic and transcriptomic combined approach has to be considered to understand this pathogenesis. © 2016 Wiley Periodicals, Inc.


Assuntos
Genômica , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Transcriptoma/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Fácies , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/fisiopatologia , Deficiências da Aprendizagem/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Front Behav Neurosci ; 8: 390, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25477793

RESUMO

Glufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Here, we addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in relative brain weight of the offspring. In addition, reduced expression of Pten and Peg3 - two genes implicated in autism-like deficits - was observed in the brain of GLA-exposed pups at postnatal day 15. Our work thus provides new data on the link between pre- and postnatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods.

16.
PLoS One ; 9(8): e105996, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25153086

RESUMO

Visual sensory impairments are common in Mental Deficiency (MD) and Autism Spectrum Disorder (ASD). These defects are linked to cerebral dysfunction in the visual cortical area characterized by the deregulation of axon growth/guidance and dendrite spine immaturity of neurons. However, visual perception had not been addressed, although the retina is part of the central nervous system with a common embryonic origin. Therefore, we investigated retinal perception, the first event of vision, in a murine model of MD with autistic features. We document that retinal function is altered in Fmr1 KO mice, a model of human Fragile X Syndrome. Indeed, In Fmr1 KO mice had a lower retinal function characterized by a decreased photoreceptors neuron response, due to a 40% decrease in Rhodopsin content and to Rod Outer Segment destabilization. In addition, we observed an alteration of the visual signal transmission between photoreceptors and the inner retina which could be attributed to deregulations of pre- and post- synaptic proteins resulting in retinal neurons synaptic destabilization and to retinal neurons immaturity. Thus, for the first time, we demonstrated that retinal perception is altered in a murine model of MD with autistic features and that there are strong similarities between cerebral and retinal cellular and molecular defects. Our results suggest that both visual perception and integration must be taken into account in assessing visual sensory impairments in MD and ASD.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Retina/fisiopatologia , Rodopsina/genética , Percepção Visual/fisiologia , Animais , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Retina/metabolismo , Rodopsina/metabolismo
17.
Orphanet J Rare Dis ; 9: 124, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25079250

RESUMO

BACKGROUND: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes. METHODS AND RESULTS: We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro, acute BMS-204352 treatment (10 µM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice. CONCLUSION: These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/prevenção & controle , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/fisiologia , Animais , Síndrome do Cromossomo X Frágil/genética , Humanos , Camundongos , Camundongos Knockout , Fenótipo
18.
PLoS One ; 9(6): e90852, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24603971

RESUMO

Delineating candidate genes at the chromosomal breakpoint regions in the apparently balanced chromosome rearrangements (ABCR) has been shown to be more effective with the emergence of next-generation sequencing (NGS) technologies. We employed a large-insert (7-11 kb) paired-end tag sequencing technology (DNA-PET) to systematically analyze genome of four patients harbouring cytogenetically defined ABCR with neurodevelopmental symptoms, including developmental delay (DD) and speech disorders. We characterized structural variants (SVs) specific to each individual, including those matching the chromosomal breakpoints. Refinement of these regions by Sanger sequencing resulted in the identification of five disrupted genes in three individuals: guanine nucleotide binding protein, q polypeptide (GNAQ), RNA-binding protein, fox-1 homolog (RBFOX3), unc-5 homolog D (C.elegans) (UNC5D), transmembrane protein 47 (TMEM47), and X-linked inhibitor of apoptosis (XIAP). Among them, XIAP is the causative gene for the immunodeficiency phenotype seen in the patient. The remaining genes displayed specific expression in the fetal brain and have known biologically relevant functions in brain development, suggesting putative candidate genes for neurodevelopmental phenotypes. This study demonstrates the application of NGS technologies in mapping individual gene disruptions in ABCR as a resource for deciphering candidate genes in human neurodevelopmental disorders (NDDs).


Assuntos
Pontos de Quebra do Cromossomo , Deficiências do Desenvolvimento/genética , Transtornos do Desenvolvimento da Linguagem/genética , Sequência de Bases , Inversão Cromossômica , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA , Translocação Genética
19.
Hum Mutat ; 35(3): 377-83, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24357492

RESUMO

Copy number gains at Xq28 are a frequent cause of X-linked intellectual disability (XLID). Here, we report on a recurrent 0.5 Mb tandem copy number gain at distal Xq28 not including MECP2, in four male patients with nonsyndromic mild ID and behavioral problems. The genomic region is duplicated in two families and triplicated in a third reflected by more distinctive clinical features. The X-inactivation patterns in carrier females correspond well with their clinical symptoms. Our mapping data confirm that this recurrent gain is likely mediated by nonallelic homologous recombination between two directly oriented Int22h repeats. The affected region harbors eight genes of which RAB39B encoding a small GTPase, was the prime candidate since loss-of-function mutations had been linked to ID. RAB39B is expressed at stable levels in lymphocytes from control individuals, suggesting a tight regulation. mRNA levels in our patients were almost two-fold increased. Overexpression of Rab39b in mouse primary hippocampal neurons demonstrated a significant decrease in neuronal branching as well as in the number of synapses when compared with the control neurons. Taken together, we provide evidence that the increased dosage of RAB39B causes a disturbed neuronal development leading to cognitive impairment in patients with this recurrent copy number gain.


Assuntos
Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Proteínas rab de Ligação ao GTP/genética , Animais , Bélgica , Diferenciação Celular , Criança , Mapeamento Cromossômico , Estônia , Duplicação Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Neurônios/citologia , Neurônios/metabolismo , População Branca , Inativação do Cromossomo X
20.
Eur J Med Genet ; 56(11): 635-41, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24013099

RESUMO

7qter deletion syndrome includes prenatal and/or postnatal growth retardation, microcephaly, psychomotor delay or mental retardation and a characteristic dysmorphism. If clinical features are well described, the molecular mechanisms underlying the 7qter deletion syndrome remain unknown. Those deletions usually arise de novo. Here, we describe a young boy with an abnormal phenotype consistent with a 7qter deletion syndrome. High resolution genomic analysis (Affymetrix Human Genome Wide SNP 6.0) revealed a 7q36.3 deletion encompassing NCAPG2, ESYT2, WDR60 and VIPR2, inherited from his asymptomatic father and paternal grandfather. In addition, the patient also harbored a MCPH1 deletion inherited from his healthy mother. Combined NCAPG2 and MCPH1 deletions were correlated with low mRNA levels and protein expression in the patient. MCPH1 and NCAPG2 proteins interaction is known to control chromosome structure and we thus propose that double heterozygosity for null mutations of those two genes of the Condensin II system contribute to mental deficiency with severe microcephaly phenotype.


Assuntos
Adenosina Trifosfatases/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/genética , Deleção de Genes , Deficiência Intelectual/genética , Microcefalia/genética , Complexos Multiproteicos/genética , Proteínas do Tecido Nervoso/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular , Criança , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos Par 7/genética , Proteínas do Citoesqueleto , Proteínas de Ligação a DNA/metabolismo , Loci Gênicos/genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Microcefalia/diagnóstico , Complexos Multiproteicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Síndrome
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