RESUMO
This paper focuses on the question of, "When is the best time to identify an individual at risk for a treatable genetic condition?" In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a "Genomics Passbook" is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a "living document" that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.
Assuntos
Testes Genéticos , Longevidade , Recém-Nascido , Humanos , CriançaRESUMO
Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery and gene editing systems. Early successes are encouraging, however, given the substantial number of distinct rare diseases, the ability to scale these successes will be unsustainable without new development efficiencies. Herein, we discuss the need for genomic newborn screening to match pace with the growing development of targeted therapeutics and ability to rapidly develop individualized therapies for rare variants. We offer approaches to move beyond conventional "one disease at a time" preclinical and clinical drug development and discuss planned regulatory innovations that are necessary to speed therapy delivery to individuals in need. These proposals leverage the shared properties of platform classes of therapeutics and innovative trial designs including master and platform protocols to better serve patients and accelerate drug development. Ultimately, there are risks to these novel approaches; however, we believe that close partnership and transparency between health authorities, patients, researchers, and drug developers present the path forward to overcome these challenges and deliver on the promise of gene-targeted therapies for rare diseases.
Assuntos
Edição de Genes , Doenças Raras , Recém-Nascido , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/terapia , Terapia Genética/métodos , GenômicaRESUMO
The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.
Assuntos
Terapia Genética , Doenças Raras , Humanos , Doenças Raras/genética , Doenças Raras/terapiaRESUMO
The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop titled "Next generation strategies for gene-targeted therapies of central nervous system (CNS) disorders" in September 2019 in Bethesda, MD, USA. The meeting brought together a multi-disciplinary group of experts in the field of CNS-directed gene-targeted therapy delivery from academia, industry, advocacy, and the government. The group was charged with identifying the key challenges and gaps in this evolving field, as well as suggesting potential solutions. The workshop was divided into four sessions: (1) control of level and location, (2) improving delivery and distribution, (3) enhancing models and manufacturing, and (4) impacting patients. Prior to the workshop, NINDS established working groups of key opinion leaders (KOLs) for each session. In pre-meeting teleconferences, KOLs were tasked with identifying the research gaps and key obstacles that delay and/or prevent gene-targeted therapies to move into the clinic. This approach allowed for the workshop to begin with problem-solving discussions and strategy development, as the key issues had been established. The overall purpose of the workshop was to consider knowledge gaps and potential strategies to inform the community around CNS gene-targeted therapies, including but not limited to researchers and funders.
Assuntos
Doenças do Sistema Nervoso Central , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/terapia , Técnicas de Transferência de Genes , Terapia Genética , HumanosRESUMO
The Hydrocephalus Association (HA) workshop, Driving Common Pathways: Extending Insights from Posthemorrhagic Hydrocephalus, was held on November 4 and 5, 2019 at Washington University in St. Louis. The workshop brought together a diverse group of basic, translational, and clinical scientists conducting research on multiple hydrocephalus etiologies with select outside researchers. The main goals of the workshop were to explore areas of potential overlap between hydrocephalus etiologies and identify drug targets that could positively impact various forms of hydrocephalus. This report details the major themes of the workshop and the research presented on three cell types that are targets for new hydrocephalus interventions: choroid plexus epithelial cells, ventricular ependymal cells, and immune cells (macrophages and microglia).
Assuntos
Hemorragia Cerebral , Hidrocefalia , Humanos , Hemorragia Cerebral/metabolismo , Plexo Corióideo/metabolismoRESUMO
Schizophrenia is a severely debilitating psychiatric disease that is hypothesized to have its roots in neurodevelopment. Although the precise neuropathology underlying schizophrenia has remained elusive, there are consistent reports of abnormalities in several brain areas. Chief among these is the hippocampus, an area which has displayed both structural and functional abnormalities in many schizophrenic patients. In order to better understand how disruption of hippocampal development may contribute to the etiology of psychiatric disease, we investigated the function of a highly promising schizophrenia susceptibility gene, DISC1 (Disrupted-In-Schizophrenia 1), in the development of the hippocampus. DISC1 is strongly expressed in the hippocampus from its early development through adulthood and has been implicated in hippocampal structure and function in human studies. However, its precise role in the development of the hippocampus is not yet known. Here, we show that in utero electroporation of Disc1 shRNA into the developing mouse hippocampus hinders the migration of dentate gyrus granule cells. Intriguingly, Disc1 knockdown does not affect the migration of CA1 pyramidal neurons, suggesting that Disc1's role in regulating neuronal migration is spatially restricted within the hippocampus. These findings support the idea that DISC1 abnormalities that contribute to the onset of schizophrenia may do so through their influences on hippocampal development.
Assuntos
Movimento Celular , Hipocampo/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Esquizofrenia/metabolismo , Animais , Linhagem Celular , Feminino , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Esquizofrenia/genética , Esquizofrenia/fisiopatologiaRESUMO
Lipid movement between organelles is a critical component of eukaryotic membrane homeostasis. Niemann Pick type C (NP-C) disease is a fatal neurodegenerative disorder typified by lysosomal accumulation of cholesterol and sphingolipids. Expression of yeast NP-C-related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation. Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Moreover, plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. We propose that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Esfingolipídeos/metabolismo , Esteróis/metabolismo , Sequência de Aminoácidos , Animais , Transporte Biológico/fisiologia , Células CHO , Membrana Celular/metabolismo , Cricetinae , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Dados de Sequência Molecular , Proteína C1 de Niemann-Pick , Doenças de Niemann-Pick/genética , Doenças de Niemann-Pick/metabolismo , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/genética , Alinhamento de Sequência , Frações Subcelulares/química , Frações Subcelulares/metabolismo , Proteínas de Transporte VesicularRESUMO
In recent years, Disrupted-In-Schizophrenia 1 (DISC1) has emerged as one of the most promising candidate genes whose disruption confers an increased risk for schizophrenia. Cell biology studies have implicated DISC1 in key neurodevelopmental processes including neurite outgrowth and neuronal migration. In situ hybridization analysis has revealed that Disc1 is expressed in the hypothalamus, olfactory bulbs, the developing cerebral cortex and the hippocampus. The hippocampus is of particular interest because abnormalities in hippocampal volume and function have been consistently reported in schizophrenics. Moreover, DISC1 mutations have been associated with abnormal activation of the hippocampus in humans. Given the involvement of the hippocampus in the pathophysiology of schizophrenia, there is an intriguing possibility that disruption of DISC1 may increase schizophrenia susceptibility by altering the normal development and function of the hippocampus. In order to contribute to our understanding of DISC1's role in the hippocampus, we have performed a detailed analysis of the Disc1 expression pattern in the mouse hippocampus throughout development. We report that Disc1 is expressed throughout the hippocampus during embryonic development, with expression becoming increasingly specialized in Ammon's horn and dentate gyrus granule cells within the first postnatal week. This expression pattern remains consistent into adulthood, with a noted decrease in Disc1 expression in the adult CA1. Disc1 is also expressed in proliferating cells in the adult subgranular zone, as well as in a subset of GABAergic interneurons. Our results are the first report of a detailed immunohistochemical analysis of the ontogeny of Disc1 expression within the hippocampus.
Assuntos
Giro Denteado/metabolismo , Hipocampo/embriologia , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Adulto , Expressão Gênica , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Imuno-Histoquímica , Células Piramidais/metabolismoRESUMO
The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop was held on July 25 and 26, 2016 at the National Institutes of Health. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood-brain and blood-CSF barriers. The goals of the workshop were to identify areas of opportunity in posthemorrhagic hydrocephalus research and encourage scientific collaboration across a diverse set of fields. This report details the major themes discussed during the workshop and research opportunities identified for posthemorrhagic hydrocephalus. The primary areas include (1) preventing intraventricular hemorrhage, (2) stopping primary and secondary brain damage, (3) preventing hydrocephalus, (4) repairing brain damage, and (5) improving neurodevelopment outcomes in posthemorrhagic hydrocephalus.
Assuntos
Hemorragia Cerebral/complicações , Hemorragia Cerebral/prevenção & controle , Hidrocefalia/etiologia , Hidrocefalia/prevenção & controle , Animais , Hemorragia Cerebral/fisiopatologia , Ensaios Clínicos como Assunto , Congressos como Assunto , Humanos , Hidrocefalia/fisiopatologiaRESUMO
Disrupted in Schizophrenia-1 (DISC1) was identified as truncated by a balanced translocation segregating with schizophrenia and other major mental illness in a large Scottish family. As a step in evaluating the function of DISC1 and its potential role in human schizophrenia, we have determined its regional expression in the primate brain by in situ hybridization. DISC1 expression is highly localized, with most prominent expression in the dentate gyrus of the hippocampus and lateral septum, and lower levels of expression in the cerebral cortex, amygdala, paraventricular hypothalamus, cerebellum, interpeduncular nucleus, and subthalamic nucleus. Given that many of these regions have been implicated in schizophrenia pathogenesis, these results suggest brain circuits through which DISC1 truncation may predispose to schizophrenia.
Assuntos
Regulação da Expressão Gênica/fisiologia , Sistema Límbico/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Esquizofrenia/metabolismo , Animais , Autorradiografia , Chlorocebus aethiops , Humanos , Hibridização In Situ , Masculino , Proteínas do Tecido Nervoso/genéticaRESUMO
Mutations in the LIS1 (Lissencephaly-1) gene underlie classical lissencephaly. This neurodevelopmental disorder is characterized by a loss of cortical gyri and improper laminar formation of the brain due to impaired neuronal migration. Patients with type 1 lissecephaly present with mental retardation and an increased risk of developing other disorders resulting from abnormal neurodevelopment, such as epilepsy. LIS1 is a dynamic protein implicated in numerous cellular mechanisms important for brain development. We have cloned and characterized the orthologs of LIS1 in the zebrafish. The zebrafish is a well-documented model organism for studies of brain development and offers many advantages including embryonic transparency, the ability to easily manipulate gene expression and also generate transgenic animals which can be used to track single, migrating neurons. In the zebrafish nervous system, the LIS1 orthologs are expressed in overlapping temporal and partially overlapping spatial patterns. While lis1a is primarily expressed in the developing central nervous system and the eye, lis1b is highly expressed in the peripheral nervous system as well as the Rohon-beard neurons. Rohon-beard neurons are the early sensory system of the embryo. We postulate that understanding the functions of Lis1 in the whole embryo will provide better insight into the genetic and neurodevelopmental basis of lissencephaly. This will not only aid in the development of therapeutic interventions for diseases such as lissencephaly but will also contribute to the general understanding of brain development.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Lisencefalia/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Sistema Nervoso/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Clonagem Molecular , Biologia Computacional , Regulação da Expressão Gênica no Desenvolvimento/genética , Imuno-Histoquímica , Hibridização In Situ , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Peixe-Zebra/genéticaRESUMO
Schizophrenia is a devastating disorder caused by both genetic and environmental factors that disrupt brain development and function. It is distinguished as a neurodevelopmental disorder in part due to early cognitive impairments, behavioral dysfunction in childhood and adolescence, and abnormalities in central nervous system development. Zebrafish are recognized as an important vertebrate model for human development and disease. There are many advantages of using zebrafish as a model, such as low cost to maintain, rapid life cycle, optical clarity and rapid external embryonic development. Furthermore, multiple molecular genetic techniques have been developed to readily study gene function during development. In this review, we will discuss the advantages of using the zebrafish model system to study schizophrenia.
Assuntos
Encéfalo/embriologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Esquizofrenia/genética , Peixe-Zebra/genética , Animais , Encéfalo/crescimento & desenvolvimento , Linhagem da Célula/genética , Movimento Celular/genética , Proteínas do Tecido Nervoso/genética , Neuregulina-1/genética , Neurogênese/genéticaRESUMO
This work reports the characterization and functional analysis of disrupted in schizophrenia 1 (disc1), a well-documented schizophrenia-susceptibility gene, in zebrafish cranial neural crest (CNC). Our data demonstrated that disc1 was expressed in zebrafish CNC cells. Loss of Disc1 resulted in persistent CNC cell medial migration, dorsal to the developing neural epithelium, and hindered migration away from the region dorsal to the neural rod. General CNC cell motility was not affected by Disc1 knockdown, however, as the speed of CNC cells was indistinguishable from that of wild-type counterparts. We determined that the failure of CNC cells to migrate away from the neural rod correlated with the enhanced expression of two transcription factors, foxd3 and sox10. These transcription factors have many functions in CNC cells, including the maintenance of precursor pools, timing of migration onset, and the induction of cell differentiation. Our work, in conjunction with previous studies, suggests that the perpetuation of expression of these factors affects several aspects of CNC cell development, leading to a loss of craniofacial cartilage and an expansion of peripheral cranial glia. Based on our data, we propose a model in which Disc1 functions in the transcriptional repression of foxd3 and sox10, thus mediating CNC cell migration and differentiation.
Assuntos
Diferenciação Celular , Movimento Celular , Fatores de Transcrição Forkhead/genética , Proteínas do Tecido Nervoso/metabolismo , Crista Neural/citologia , Fatores de Transcrição SOXE/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Proteínas do Tecido Nervoso/genética , Crista Neural/efeitos dos fármacos , Neuroglia/citologia , Neuroglia/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Sítios de Splice de RNA , Fatores de Transcrição SOXE/metabolismo , Homologia de Sequência de Aminoácidos , Crânio/citologia , Crânio/metabolismo , Fatores de Tempo , Peixe-Zebra/genéticaRESUMO
NudE-Like (NDEL1/NUDEL), through its interaction with LIS1 and DISC1, has been implicated in the etiology of neurological disorders such as lissencephaly and schizophrenia, respectively. Subsequently, a large portion of the research done on the function of NDEL1 has been specifically targeted to its role in brain development while ignoring its function in other developing and adult tissues. To begin a more global exploration of NDEL1's function, this study characterizes the developmental expression pattern of the NDEL1 orthologs in the zebrafish embryo. Our bioinformatic analyses identified two NDEL1 orthologs in the zebrafish, ndel1a and ndel1b. ndel1a is expressed predominantly in the anterior central nervous system (CNS), trigeminal ganglia, and eyes while ndel1b is expressed in the developing somites and, later, in the CNS. In addition to the spatial differences in their expression patterns, these genes are also individually regulated in their temporal expression. Both are expressed maternally but at later time-points there are subtle differences. ndel1a expression is lost between 6 and 12 hpf but then increases to a higher, near steady state, level from 72 to 120 hpf. ndel1b expression decreases from 3 to 36 hpf and subsequently increases from 36 to 120 hpf. The non-overlapping expression patterns of these two orthologs may indicate that they have split the functional role of the one NDEL1 gene present in mammalian species. The temporal and spatial regulation of these two orthologs will aid in the characterization of the multiple functions of this gene in both the developing and mature organism.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Proteínas de Transporte/genética , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/fisiologia , Cerebelo/fisiologia , Clonagem Molecular , Embrião não Mamífero , Feminino , Perfilação da Expressão Gênica , Humanos , Lisencefalia/genética , Camundongos , Dados de Sequência Molecular , Células de Purkinje/fisiologia , Especificidade da Espécie , Gânglio Trigeminal/embriologia , Gânglio Trigeminal/crescimento & desenvolvimento , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
Disrupted-In-Schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain.
Assuntos
Centrossomo/ultraestrutura , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/fisiologia , Serina Endopeptidases/metabolismo , Fatores de Transcrição/metabolismo , Fatores Ativadores da Transcrição , Linhagem Celular , Linhagem Celular Tumoral , Centrossomo/metabolismo , DNA Complementar/metabolismo , Deleção de Genes , Biblioteca Gênica , Células HeLa , Humanos , Imuno-Histoquímica , Microtúbulos/metabolismo , Modelos Biológicos , Modelos Genéticos , Neurônios/metabolismo , Testes de Precipitina , Ligação Proteica , Estrutura Terciária de Proteína , Esquizofrenia/genética , Transdução de Sinais , Sindbis virus/genética , Frações Subcelulares/metabolismo , Distribuição Tecidual , Transfecção , Técnicas do Sistema de Duplo-HíbridoRESUMO
Demonstration that cleavage of both APP and Notch are dependent on the product of the early onset Alzheimer's disease gene, presenilin-1 (PS1), has raised the possibility that Notch function may be altered in AD. This finding also suggests that Notch may be affected by APPgamma-secretase inhibitors under development for the treatment of Alzheimer's disease, as these target PS1. Data that address these questions have been lacking, due to inability to specifically modulate PS1 activity in a system directly relevant to the adult human brain. Using novel highly specific inhibitors of PS1/gamma-secretase, we demonstrate that modulation of PS1 activity in human CNS neurons not only affects Abeta generation, but also has unanticipated effects on Notch and its activity. We demonstrate that intracellular trafficking of Notch in human CNS neurons is altered by inhibition of PS1 and is accompanied by dramatic changes in neurite morphology, consistent with inhibition of Notch activity. These data, together with immunohistochemical evidence of elevation of Notch pathway expression in AD brain, suggest that Notch dysregulation may contribute to the neuritic dystrophy characteristically seen in Alzheimer's disease brain. In addition, they raise the possibility that inhibition of gamma-secretase/PS1 may have clinically beneficial effects on the neuritic pathology of AD, in addition to its expected effect to reduce amyloid burden.
Assuntos
Endopeptidases/metabolismo , Proteínas de Membrana/metabolismo , Neuritos/fisiologia , Receptores de Superfície Celular , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Proteínas Quinases Dependentes de Cálcio-Calmodulina/análise , Carbamatos/farmacologia , Dipeptídeos/farmacologia , Proteínas Desgrenhadas , Retículo Endoplasmático/metabolismo , Quinase 3 da Glicogênio Sintase , Complexo de Golgi/metabolismo , Hipocampo/química , Hipocampo/metabolismo , Humanos , Macaca mulatta , Proteínas de Membrana/análise , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Neuritos/patologia , Neuroblastoma , Fosfoproteínas/análise , Presenilina-1 , Inibidores de Proteases/farmacologia , Receptor Notch1 , Células Tumorais CultivadasRESUMO
We cloned the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1), a candidate gene for schizophrenia. Disc1 is 3163 nucleotides long and has 60% identity with the human DISC1. Disc1 encodes 851 amino acids and has 56% identity with the human protein. Disc1 maps to the DISC1 syntenic region in the mouse, and genomic structure is conserved. A Disc1 splice variant deletes a portion of Disc1 beginning at amino acids orthologous to the human truncation. Bioinformatic analysis and cross-species comparisons revealed sequence conservation distributed across the genes and conservation of leucine zipper and coiled-coil domains in both orthologs. In situ hybridization in adult mouse brain revealed a restricted expression pattern, with highest levels in the dentate gyrus of the hippocampus and lower expression in CA1-CA3 of the hippocampus, cerebellum, cerebral cortex, and olfactory bulbs. Identification of Disc1 will facilitate the study of DISC1's function and creation of mouse models of DISC1 disruption.