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1.
Genet Med ; 24(9): 1952-1966, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35916866

RESUMEN

PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.


Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Encéfalo/metabolismo , Regulación de la Expresión Génica , Humanos , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Dominios Proteicos , Secuenciación del Exoma
2.
N Engl J Med ; 378(11): 1018-1028, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29539279

RESUMEN

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).


Asunto(s)
Mutación , Epilepsia Mioclónica Juvenil/genética , Proteínas Serina-Treonina Quinasas/genética , Adolescente , Animales , Teorema de Bayes , Estudios de Casos y Controles , Niño , Preescolar , Cromosomas Humanos Par 6 , Modelos Animales de Enfermedad , Electroencefalografía , Femenino , Heterocigoto , Humanos , Lactante , Recién Nacido , Masculino , Malformaciones del Desarrollo Cortical/genética , Ratones , Ratones Noqueados , Epilepsia Mioclónica Juvenil/fisiopatología , Análisis de Secuencia de ADN , Adulto Joven
3.
Epilepsia ; 62(6): 1391-1400, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33913524

RESUMEN

OBJECTIVE: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population. METHODS: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data. RESULTS: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10-10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24. SIGNIFICANCE: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.


Asunto(s)
Cromosomas Humanos Par 12/genética , Epilepsia/genética , Estudio de Asociación del Genoma Completo , Pueblo Asiatico , Estudios de Casos y Controles , Epilepsia/epidemiología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Japón/epidemiología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
4.
Hum Mol Genet ; 26(24): 4961-4974, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29040524

RESUMEN

Genetic studies point to a major role of de novo mutations in neurodevelopmental disorders of intellectual disability, autism spectrum disorders, and epileptic encephalopathy. The STXBP1 gene encodes the syntaxin-binding protein 1 (Munc18-1) that critically controls synaptic vesicle exocytosis and synaptic transmission. This gene harbors a high frequency of de novo mutations, which may play roles in these neurodevelopmental disorders. However, the system and behavioral-level pathophysiological changes caused by these genetic defects remain poorly understood. Constitutional (Stxbp1+/-), dorsal-telencephalic excitatory (Stxbp1fl/+/Emx), or global inhibitory neuron-specific (Stxbp1fl/+/Vgat) mice were subjected to a behavioral test battery examining locomotor activity, anxiety, fear learning, and social interactions including aggression. Furthermore, measurements of local field potentials in multiple regions of the brain were performed. Stxbp1+/- male mice exhibited enhanced aggressiveness and impaired fear learning associated with elevated gamma activity in several regions of the brain including the prefrontal cortex. Stxbp1fl/+/Emx mice showed fear-learning deficits, but neither Stxbp1fl/+/Emx nor Stxbp1fl/+/Vgat mice showed increased aggressiveness. Pharmacological potentiation of the excitatory transmission at active synapses via the systemic administration of ampakine CX516, which enhances the excitatory postsynaptic function, ameliorated the aggressive phenotype of Stxbp1+/- mice. These findings suggest that synaptic impairments of the dorsal telencephalic and subcortical excitatory neurons cause learning deficits and enhanced aggression in Stxbp1+/- mice, respectively. Additionally, normalizing the excitatory synaptic transmission is a potential therapeutic option for managing aggressiveness in patients with STXBP1 mutations.


Asunto(s)
Proteínas Munc18/metabolismo , Transmisión Sináptica/fisiología , Agresión/fisiología , Animales , Encéfalo/metabolismo , Dioxoles/farmacocinética , Potenciales Postsinápticos Excitadores/fisiología , Haploinsuficiencia , Discapacidad Intelectual/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Munc18/genética , Proteínas Munc18/fisiología , Trastornos del Neurodesarrollo/metabolismo , Neuronas/metabolismo , Piperidinas/farmacocinética , Sinapsis/metabolismo
5.
Genet Med ; 19(2): 144-156, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27467453

RESUMEN

PURPOSE: EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS: We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS: Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS: NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.


Asunto(s)
Proteínas de Unión al Calcio/genética , Epilepsia Mioclónica Juvenil/genética , Convulsiones/genética , Animales , Dendritas/patología , Exoma , Frecuencia de los Genes , Humanos , Ratones , Ratones Noqueados , Mutación , Epilepsia Mioclónica Juvenil/fisiopatología , National Human Genome Research Institute (U.S.) , Neuronas/patología , Linaje , Polimorfismo de Nucleótido Simple , Convulsiones/fisiopatología , Sinapsis/patología , Estados Unidos
6.
Dev Psychobiol ; 59(1): 39-47, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27473368

RESUMEN

Plasticity of the axon initial segment (AIS) is a newly discovered type of structural plasticity that regulates cell excitability. AIS plasticity has been reported to happen during normal development of neocortex and also in a few pathological conditions involving disruption of the inhibition/excitation balance. Here we report on the impact of early environmental interventions on structural plasticity of AIS in the mouse neocortex. C57BL/6 mice were raised in standard or enriched environment (EE) from birth up to the time of experiments and were injected with saline or MK-801 [N-Methyl-D-Aspartate (NMDA) receptor antagonist, 1 mg/kg] on postnatal days (P) 6-10. We used Ankyrin G immunoreactivity to mark the AIS of cortical neurons in two sub-regions of frontal cortex (frontal association area, FrA and secondary motor cortex, M2) and in the secondary visual cortex (V2). In 1-month-old mice, the mean AIS length differed between three areas, with the shortest AISs being observed in V2. Postnatal MK-801 or EE led to shortening of AIS only in the frontal areas. However, exposure to EE restored AIS shortening induced by MK-801. Chronic postnatal MK-801 results in structural plasticity of AIS exclusive to the frontal cortex. EE may modify underlying neuronal mechanisms resulting in restoration of AIS length.


Asunto(s)
Segmento Inicial del Axón/fisiología , Maleato de Dizocilpina/farmacología , Ambiente , Antagonistas de Aminoácidos Excitadores/farmacología , Neocórtex/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Segmento Inicial del Axón/efectos de los fármacos , Maleato de Dizocilpina/administración & dosificación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Neocórtex/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos
7.
Hum Mol Genet ; 21(1): 175-84, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21965301

RESUMEN

Lafora progressive myoclonus epilepsy (also known as Lafora disease, LD) is an inherited and fatal form of a neurodegenerative disorder characterized by the presence of carbohydrate-rich inclusions called Lafora bodies. LD can be caused by defects in the laforin phosphatase or the malin ubiquitin ligase and the clinical symptoms resulting from these two defects are almost similar. In order to understand the molecular basis of LD pathogenesis and the role of Lafora bodies in neuropathology, we have studied the laforin-deficient mice as a model and show here that Lafora bodies recruit proteasomal subunit, endoplasmic reticulum chaperone GRP78/Bip, autophagic protein p62 and endosomal regulators Rab5 and Rab7. The laforin-deficient brain also reveals the proliferation of enlarged lysosomes, lipofuscin granules, amyloid-ß peptides and increased levels of insoluble form of ubiquitinated protein, indicating a significant impairment in the cellular degradative pathway. Further, abnormal dendrites and increased gliosis, especially at the vicinity of Lafora bodies, were noted in the LD brain. Taken together, our study suggests that the neuropathology in LD is not limited to Lafora bodies, that some of the neuropathological changes in LD are likely to be secondary effects caused by Lafora bodies, and that impairment in the autophagy-endosomal-lysosomal pathways might underlie some of the symptoms in LD.


Asunto(s)
Autofagia , Modelos Animales de Enfermedad , Endosomas/metabolismo , Enfermedad de Lafora/metabolismo , Enfermedad de Lafora/fisiopatología , Lisosomas/metabolismo , Animales , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Chaperón BiP del Retículo Endoplásmico , Endosomas/genética , Endosomas/patología , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Enfermedad de Lafora/genética , Enfermedad de Lafora/patología , Lisosomas/genética , Lisosomas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Tirosina Fosfatasas no Receptoras
8.
Mol Neurobiol ; 61(2): 622-634, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37650965

RESUMEN

Numerous pathogenic variants of SCN2A gene, encoding voltage-gated sodium channel α2 subunit Nav1.2 protein, have been identified in a wide spectrum of neuropsychiatric disorders including schizophrenia. However, pathological mechanisms for the schizophrenia-relevant behavioral abnormalities caused by the variants remain poorly understood. Here in this study, we characterized mouse lines with selective Scn2a deletion at schizophrenia-related brain regions, medial prefrontal cortex (mPFC) or ventral tegmental area (VTA), obtained by injecting adeno-associated viruses (AAV) expressing Cre recombinase into homozygous Scn2a-floxed (Scn2afl/fl) mice, in which expression of the Scn2a was locally deleted in the presence of Cre recombinase. The mice lacking Scn2a in the mPFC exhibited a tendency for a reduction in prepulse inhibition (PPI) in acoustic startle response. Conversely, the mice lacking Scn2a in the VTA showed a significant increase in PPI. We also found that the mice lacking Scn2a in the mPFC displayed increased sociability, decreased locomotor activity, and increased anxiety-like behavior, while the mice lacking Scn2a in the VTA did not show any other abnormalities in these parameters except for vertical activity which is one of locomotor activities. These results suggest that Scn2a-deficiencies in mPFC and VTA are inversely relevant for the schizophrenic phenotypes in patients with SCN2A variants.


Asunto(s)
Inhibición Prepulso , Reflejo de Sobresalto , Ratones , Humanos , Animales , Área Tegmental Ventral/fisiología , Corteza Prefrontal/metabolismo , Acústica
9.
Cell Metab ; 7(4): 302-11, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18396136

RESUMEN

Peroxisome proliferator-activated receptor gamma (PPARgamma) is induced in leptin-deficient (ob/ob) mouse liver and is critical for the development of hepatic steatosis. The present study shows that fat-specific protein 27 (Fsp27) in ob/ob liver is a direct target gene of PPARgamma and can elevate hepatic triglyceride levels. FSP27 belongs to the CIDE family, composed of CIDE A, CIDE B, and FSP27/CIDE C, all of which contain a conserved CIDE-N domain. FSP27 was recently reported to be a lipid droplet-binding protein and to promote lipid accumulation in adipocytes. The Fsp27 gene was expressed at high levels in ob/ob liver and at markedly lower levels in ob/ob livers lacking PPARgamma. Forced expression of FSP27 by adenovirus in hepatocytes in vitro or in vivo led to increased triglyceride levels. Knockdown by adenovirus expressing FSP27 shRNA resulted in lower accumulation of hepatic triglycerides compared to control adenovirus-infected liver. Taken together, these results indicate that FSP27 is a direct mediator of PPARgamma-dependent hepatic steatosis.


Asunto(s)
Hígado Graso/metabolismo , Leptina/deficiencia , PPAR gamma/metabolismo , Proteínas/metabolismo , Adenoviridae/genética , Adipocitos/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Células Cultivadas , Hígado Graso/genética , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Leptina/metabolismo , Ratones , Regiones Promotoras Genéticas , Proteínas/genética , ARN/metabolismo , Triglicéridos/metabolismo
10.
Epilepsy Behav ; 28 Suppl 1: S61-2, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23756482

RESUMEN

Mutations in EFHC1 gene cause juvenile myoclonic epilepsy (JME). We previously showed that myoclonin1 protein encoded by EFHC1 is expressed in prenatal choroid plexus and postnatal ependymal cell cilia but may not be in neurons. However, another group reported that myoclonin1 is expressed in neurons and at mitotic spindle, and that the suppression of EFHC1 by RNAi caused disruption of mitotic spindle structure, impaired M-phase progression, and an increase of apoptosis. We re-investigated their results by using the same polyclonal antibody that they used, and found that the signals in neurons remained in Efhc1-deficient mouse, suggesting that the signals in neurons were nonspecific. Furthermore, Efhc1 (-/-) mouse did not show any abnormalities such as disruption of mitotic spindle structure, impaired M-phase progression, and an increase of apoptosis. Further investigations are required to clarify these discrepancies.


Asunto(s)
Proteínas de Unión al Calcio/genética , Epilepsia Mioclónica Juvenil/genética , Epilepsia Mioclónica Juvenil/patología , Neuronas/metabolismo , Transducción de Señal/inmunología , Animales , Proteínas de Unión al Calcio/deficiencia , Ciclo Celular/genética , Ciclo Celular/inmunología , Humanos , Ratones , Ratones Noqueados , Mutación/genética , Neuronas/ultraestructura , Interferencia de ARN/fisiología , Huso Acromático/genética
11.
Nat Genet ; 36(8): 842-9, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15258581

RESUMEN

Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca(2+) channel (Ca(v)2.3). EFHC1 and Ca(v)2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Ca(v)2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca(2+) currents that were reversed by the mutations associated with JME.


Asunto(s)
Epilepsia Mioclónica Juvenil/genética , Animales , Apoptosis/genética , Proteínas de Unión al Calcio/genética , Células Cultivadas , Humanos , Ratones , Datos de Secuencia Molecular , Mutación Missense , Linaje
12.
J Contemp Dent Pract ; 14(6): 1137-44, 2013 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-24858764

RESUMEN

AIM: To investigate and compare the effects of toothbrushes with different hardness on abrasion and surface roughness of composite resins. MATERIALS AND METHODS: Toothbrushes (DENT. EX Slimhead II 33, Lion Dental Products Co. Ltd., Tokyo, Japan) marked as soft, medium and hard, were used to brush 10 beam-shaped specimens of each of three composites resins (Venus [VEN], Venus Diamond [VED] and Venus Pearl [VEP]; HeraeusKulzer) with standardized calcium carbonate slurry in a multistation testing machine (2N load, 60 Hz). After each of five cycles with 10k brushing strokes the wear depth and surface roughness of the specimens were determined. After completion of 50k strokes representative samples were inspected by SEM. Data were treated with ANOVA and regression analyses (p < 0.05). RESULTS: Abrasion of the composite resins increased linearly with increasing number of brushing cycles (r² > 0.9). Highest wear was recorded for VEN, lowest for VED. Hard brushes produced significantly higher wear on VEN and VEP, whereas no difference in wear by toothbrush type was detected for VED. Significantly highest surface roughness was found on VED specimens (Ra > 1.5 µm), the lowest one on VEN (Ra < 0.3 µm). VEN specimens showed increased numbers of pinhole defects when brushed with hard toothbrushes, surfaces of VEP were uniformly abraded without level differences between the prepolymerized fillers and the glass filler-loaded matrix, VED showed large glass fillers protruding over the main filler-loaded matrix portion under each condition. CONCLUSION: Abrasion and surface roughness of composite resins produced by toothbrushing with dentifrice depend mainly on the type of restorative resin. Hardness grades of toothbrushes have minor effects only on abrasion and surface roughness of composite resins. No relationship was found between abrasion and surface roughness. CLINICAL SIGNIFICANCE: The grade of the toothbrush used has minor effect on wear, texture and roughness of the composite resin.


Asunto(s)
Resinas Compuestas/química , Materiales Dentales/química , Cepillado Dental/instrumentación , Compuestos de Bario/química , Bisfenol A Glicidil Metacrilato/química , Carbonato de Calcio/química , Diseño de Equipo , Dureza , Humanos , Ensayo de Materiales , Metacrilatos/química , Microscopía Electrónica de Rastreo , Polietilenglicoles/química , Ácidos Polimetacrílicos/química , Poliuretanos/química , Dióxido de Silicio/química , Propiedades de Superficie , Pastas de Dientes/química
13.
Elife ; 122023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-37219072

RESUMEN

Expressions of voltage-gated sodium channels Nav1.1 and Nav1.2, encoded by SCN1A and SCN2A genes, respectively, have been reported to be mutually exclusive in most brain regions. In juvenile and adult neocortex, Nav1.1 is predominantly expressed in inhibitory neurons while Nav1.2 is in excitatory neurons. Although a distinct subpopulation of layer V (L5) neocortical excitatory neurons were also reported to express Nav1.1, their nature has been uncharacterized. In hippocampus, Nav1.1 has been proposed to be expressed only in inhibitory neurons. By using newly generated transgenic mouse lines expressing Scn1a promoter-driven green fluorescent protein (GFP), here we confirm the mutually exclusive expressions of Nav1.1 and Nav1.2 and the absence of Nav1.1 in hippocampal excitatory neurons. We also show that Nav1.1 is expressed in inhibitory and a subpopulation of excitatory neurons not only in L5 but all layers of neocortex. By using neocortical excitatory projection neuron markers including FEZF2 for L5 pyramidal tract (PT) and TBR1 for layer VI (L6) cortico-thalamic (CT) projection neurons, we further show that most L5 PT neurons and a minor subpopulation of layer II/III (L2/3) cortico-cortical (CC) neurons express Nav1.1 while the majority of L6 CT, L5/6 cortico-striatal (CS), and L2/3 CC neurons express Nav1.2. These observations now contribute to the elucidation of pathological neural circuits for diseases such as epilepsies and neurodevelopmental disorders caused by SCN1A and SCN2A mutations.


Asunto(s)
Neocórtex , Ratones , Animales , Ratones Transgénicos , Neocórtex/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Tractos Piramidales , Canal de Sodio Activado por Voltaje NAV1.1/genética , Neuronas/fisiología , Células Piramidales/metabolismo
14.
Sci Rep ; 12(1): 6505, 2022 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35581205

RESUMEN

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.


Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Animales , Epilepsia/genética , Estudio de Asociación del Genoma Completo , Hipocampo/metabolismo , Proteínas de Homeodominio/genética , Humanos , Ácido Kaínico , Ratones , Convulsiones/genética , Transmisión Sináptica
15.
Hum Mol Genet ; 18(6): 1099-109, 2009 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19147686

RESUMEN

Mutations in EFHC1 gene have been previously reported in patients with epilepsies, including those with juvenile myoclonic epilepsy. Myoclonin1, also known as mRib72-1, is encoded by the mouse Efhc1 gene. Myoclonin1 is dominantly expressed in embryonic choroid plexus, post-natal ependymal cilia, tracheal cilia and sperm flagella. In this study, we generated viable Efhc1-deficient mice. Most of the mice were normal in outward appearance, and both sexes were found to be fertile. However, the ventricles of the brains were significantly enlarged in the null mutants, but not in the heterozygotes. Although the ciliary structure was found intact, the ciliary beating frequency was significantly reduced in null mutants. In adult stages, both the heterozygous and null mutants developed frequent spontaneous myoclonus. Furthermore, the threshold of seizures induced by pentylenetetrazol was significantly reduced in both heterozygous and null mutants. These observations seem to further suggest that decrease or loss of function of myoclonin1 may be the molecular basis for epilepsies caused by EFHC1 mutations.


Asunto(s)
Proteínas de Unión al Calcio/deficiencia , Predisposición Genética a la Enfermedad , Mioclonía/complicaciones , Mioclonía/genética , Convulsiones/complicaciones , Convulsiones/genética , Animales , Proteínas de Unión al Calcio/metabolismo , Ventrículos Cerebrales/metabolismo , Ventrículos Cerebrales/patología , Cilios/ultraestructura , Convulsivantes , Giro Dentado/metabolismo , Giro Dentado/patología , Heterocigoto , Ratones , Mutación/genética , Mioclonía/patología , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Convulsiones/patología , Ácidos Siálicos/metabolismo , Ácido gamma-Aminobutírico/metabolismo
16.
Med Mol Morphol ; 44(4): 190-9, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22179181

RESUMEN

The prevalence of dopamine and cAMP-regulated phosphoprotein 32kD (DARPP-32) is associated with the pathogenesis of schizophrenia. To date, the findings on DARPP-32 cellular expression and distribution in postmortem brains from patients with schizophrenia have been inconsistent. To clarify the detailed cellular expression of DARPP-32 in patients with schizophrenia, we immunohistochemically stained sections from postmortem brains using specific antibodies. We measured the density of immunopositive cells in various brain regions including the prefrontal cortex and compared the data from nine schizophrenia subjects with those of nine age- and sex-matched control subjects. The density of DARPP-32-immunoreactive (IR) neurons was significantly lower in layers II-V of the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia. In contrast, there were no marked differences in DARPP-32 expression in other brain regions. In addition, the density of threonine (Thr34)-phosphorylated DARPP-32-IR neurons was significantly higher in layer V of DLPFC from subjects with schizophrenia. These results suggest that the decrease in DARPP-32 in schizophrenia was more marked in neurons of DLPFC than in other cells or other brain regions, and that this decrease might be partly compensated for by an increase in expression of Thr34-phosphorylated DARPP-32 in DLPFC.


Asunto(s)
Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Expresión Génica , Corteza Prefrontal/metabolismo , Esquizofrenia/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Células Cultivadas , Fosfoproteína 32 Regulada por Dopamina y AMPc/genética , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Corteza Prefrontal/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
Med Mol Morphol ; 44(3): 146-50, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21922386

RESUMEN

To investigate the status of fatty acid synthase (FAS) in bladder tumors and evaluate its prognostic significance, we immunohistochemically examined the expression of FAS in normal urothelium, carcinoma in situ (CIS), and urothelial carcinoma (UC) in cystectomized bladder. In normal urothelium, only the surface layer expressed FAS, whereas the protein was detected in the basal layer or whole layer of CIS and UC in every specimen. Of the clinicopathological factors in UC, pathological tumor (pT) stage and histological grade were significantly correlated to FAS expression (P = 0.002, P < 0.0001, respectively). Univariate analysis for disease-specific survival indicated that the combination scores of FAS and Ki-67 expression, which were not associated with each other, was a more predictive variable than the individual score of each protein expression. Kaplan-Meier analysis showed that high combination scores of both proteins were significantly associated with poor prognosis (P = 0.04). In conclusion, FAS expression can be a biomarker for tumor aggressiveness and loss of differentiation of bladder cancer, and the evaluation of its expression level in combination with Ki-67 labeling index may be a precise predictor for poor prognosis of cancer patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma in Situ/metabolismo , Ácido Graso Sintasas/metabolismo , Expresión Génica , Antígeno Ki-67/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Biomarcadores de Tumor/genética , Carcinoma in Situ/mortalidad , Carcinoma in Situ/patología , Carcinoma in Situ/cirugía , Estudios de Casos y Controles , Cistectomía , Ácido Graso Sintasas/genética , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/genética , Pronóstico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugía , Urotelio/patología
18.
J Biol Chem ; 284(34): 22657-63, 2009 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-19542233

RESUMEN

Lafora progressive myoclonous epilepsy (Lafora disease; LD) is caused by mutations in the EPM2A gene encoding a dual specificity protein phosphatase named laforin. Our analyses on the Epm2a gene knock-out mice, which developed most of the symptoms of LD, reveal the presence of hyperphosphorylated Tau protein (Ser(396) and Ser(202)) as neurofibrillary tangles (NFTs) in the brain. Intriguingly, NFTs were also observed in the skeletal muscle tissues of the knock-out mice. The hyperphosphorylation of Tau was associated with increased levels of the active form of GSK3 beta. The observations on Tau protein were replicated in cell lines using laforin overexpression and knockdown approaches. We also show here that laforin and Tau proteins physically interact and that the interaction was limited to the phosphatase domain of laforin. Finally, our in vitro and in vivo assays demonstrate that laforin dephosphorylates Tau, and therefore laforin is a novel Tau phosphatase. Taken together, our study suggests that laforin is one of the critical regulators of Tau protein, that the NFTs could underlie some of the symptoms seen in LD, and that laforin can contribute to the NFT formation in Alzheimer disease and other tauopathies.


Asunto(s)
Fosfatasas de Especificidad Dual/deficiencia , Enfermedad de Lafora/metabolismo , Proteínas tau/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Modelos Animales de Enfermedad , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Femenino , Immunoblotting , Inmunohistoquímica , Inmunoprecipitación , Técnicas In Vitro , Enfermedad de Lafora/genética , Ratones , Ratones Noqueados , Microscopía Electrónica , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Fosforilación/genética , Unión Proteica , Proteínas Tirosina Fosfatasas no Receptoras
20.
J Phys Chem A ; 114(11): 3845-54, 2010 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-19719174

RESUMEN

The mechanism for the dehydrogenation of ethylbenzene over V, Cr, and Fe oxides loaded on activated carbon, powdered diamond, Al(2)O(3), and MgO was studied in the presence of CO(2). Vanadium oxide-loaded catalysts provided higher styrene yields under CO(2) than Ar flow. The transient response method was carried out to understand the reaction behaviors of lattice oxygen of various metal oxides on the support. The results showed that lattice oxygen of vanadium oxide (V=O) was consumed in the dehydrogenation reaction and that reduced vanadium oxide was reoxidized with CO(2). A similar redox cycle was observed on iron oxide-loaded activated carbon catalyst. Spectroscopic characterization revealed that vanadium oxide and iron oxide on the support were reduced to a low valence state during the dehydrogenation reaction, and that CO(2) could oxidize the reduced metal oxides. In contrast, chromium(III) oxide was not reduced during dehydrogenation. From these findings, the redox cycle over vanadium oxide- and iron oxide-loaded catalysts was concluded to be an important factor in promoting the catalytic activity with CO(2).

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