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1.
Am J Hum Genet ; 108(1): 148-162, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33308442

RESUMEN

SYNGAP1 is a neuronal Ras and Rap GTPase-activating protein with important roles in regulating excitatory synaptic plasticity. While many SYNGAP1 missense and nonsense mutations have been associated with intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder (ASD), whether and how they contribute to individual disease phenotypes is often unknown. Here, we characterize 57 variants in seven assays that examine multiple aspects of SYNGAP1 function. Specifically, we used multiplex phospho-flow cytometry to measure variant impact on protein stability, pERK, pGSK3ß, pp38, pCREB, and high-content imaging to examine subcellular localization. We find variants ranging from complete loss-of-function (LoF) to wild-type (WT)-like in their regulation of pERK and pGSK3ß, while all variants retain at least partial ability to dephosphorylate pCREB. Interestingly, our assays reveal that a larger proportion of variants located within the disordered domain of unknown function (DUF) comprising the C-terminal half of SYNGAP1 exhibited higher LoF, compared to variants within the better studied catalytic domain. Moreover, we find protein instability to be a major contributor to dysfunction for only two missense variants, both located within the catalytic domain. Using high-content imaging, we find variants located within the C2 domain known to mediate membrane lipid interactions exhibit significantly larger cytoplasmic speckles than WT SYNGAP1. Moreover, this subcellular phenotype shows both correlation with altered catalytic activity and unique deviation from signaling assay results, highlighting multiple independent molecular mechanisms underlying variant dysfunction. Our multidimensional dataset allows clustering of variants based on functional phenotypes and provides high-confidence, multi-functional measures for making pathogenicity predictions.


Asunto(s)
GTP Fosfohidrolasas/genética , Mutación/genética , Transducción de Señal/genética , Proteínas Activadoras de ras GTPasa/genética , Trastorno del Espectro Autista/genética , Línea Celular , Epilepsia/genética , Células HEK293 , Humanos , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Fenotipo , Estabilidad Proteica
2.
Am J Hum Genet ; 106(2): 143-152, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32032513

RESUMEN

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.


Asunto(s)
Modelos Animales de Enfermedad , Marcadores Genéticos , Enfermedades Raras/genética , Enfermedades Raras/terapia , Sistema de Registros/normas , Animales , Bases de Datos Factuales , Genómica , Humanos , Enfermedades Raras/epidemiología
3.
Hum Mutat ; 43(6): 743-759, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35224820

RESUMEN

Next-generation sequencing is a prevalent diagnostic tool for undiagnosed diseases and has played a significant role in rare disease gene discovery. Although this technology resolves some cases, others are given a list of possibly damaging genetic variants necessitating functional studies. Productive collaborations between scientists, clinicians, and patients (affected individuals) can help resolve such medical mysteries and provide insights into in vivo function of human genes. Furthermore, facilitating interactions between scientists and research funders, including nonprofit organizations or commercial entities, can dramatically reduce the time to translate discoveries from bench to bedside. Several systems designed to connect clinicians and researchers with a shared gene of interest have been successful. However, these platforms exclude some stakeholders based on their role or geography. Here we describe ModelMatcher, a global online matchmaking tool designed to facilitate cross-disciplinary collaborations, especially between scientists and other stakeholders of rare and undiagnosed disease research. ModelMatcher is integrated into the Rare Diseases Models and Mechanisms Network and Matchmaker Exchange, allowing users to identify potential collaborators in other registries. This living database decreases the time from when a scientist or clinician is making discoveries regarding their genes of interest, to when they identify collaborators and sponsors to facilitate translational and therapeutic research.


Asunto(s)
Enfermedades no Diagnosticadas , Bases de Datos Factuales , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Sistema de Registros , Investigadores
4.
Clin Genet ; 96(3): 199-206, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31038196

RESUMEN

Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD-association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high-priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well-established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.


Asunto(s)
Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Variación Genética , Secuenciación Completa del Genoma , Alelos , Sustitución de Aminoácidos , Trastorno del Espectro Autista/diagnóstico , Colombia Británica , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Mutación , Fenotipo , Polimorfismo de Nucleótido Simple
5.
Blood ; 125(6): 959-66, 2015 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-25395426

RESUMEN

Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Index low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies.


Asunto(s)
Proteínas Co-Represoras/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Proteínas del Tejido Nervioso/genética , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Eliminación de Gen , Técnicas de Silenciamiento del Gen , Humanos , Factores Inmunológicos/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Rituximab , Transcriptoma , Vincristina/uso terapéutico
6.
Nature ; 476(7360): 298-303, 2011 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-21796119

RESUMEN

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.


Asunto(s)
Histonas/metabolismo , Linfoma no Hodgkin/genética , Mutación/genética , Cromatina/genética , Cromatina/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Genoma Humano/genética , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Pérdida de Heterocigocidad/genética , Linfoma Folicular/enzimología , Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/enzimología , Linfoma de Células B Grandes Difuso/genética , Linfoma no Hodgkin/enzimología , Proteínas de Dominio MADS/genética , Proteínas de Dominio MADS/metabolismo , Factores de Transcripción MEF2 , Factores Reguladores Miogénicos/genética , Factores Reguladores Miogénicos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
7.
Hum Mutat ; 37(8): 719-26, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27158917

RESUMEN

Identifying variants causal for complex genetic disorders is challenging. With the advent of whole-exome and whole-genome sequencing, computational tools are needed to explore and analyze the list of variants for further validation. Correlating genetic variants with subject phenotype is crucial for the interpretation of the disease-causing mutations. Often such work is done by teams of researchers who need to share information and coordinate activities. To this end, we have developed a powerful, easy to use Web application, ASPIREdb, which allows researchers to search, organize, analyze, and visualize variants and phenotypes associated with a set of human subjects. Investigators can annotate variants using publicly available reference databases and build powerful queries to identify subjects or variants of interest. Functional information and phenotypic associations of these genes are made accessible as well. Burden analysis and additional reporting tools allow investigation of variant properties and phenotype characteristics. Projects can be shared, allowing researchers to work collaboratively to build queries and annotate the data. We demonstrate ASPIREdb's functionality using publicly available data sets, showing how the software can be used to accomplish goals that might otherwise require specialized bioinformatics expertise. ASPIREdb is available at http://aspiredb.chibi.ubc.ca.


Asunto(s)
Biología Computacional/métodos , Variación Genética , Bases de Datos Genéticas , Exoma , Predisposición Genética a la Enfermedad , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fenotipo , Navegador Web
8.
Alcohol Clin Exp Res ; 40(4): 717-27, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26996386

RESUMEN

BACKGROUND: Prenatal alcohol exposure (PAE) can result in an array of morphological, behavioral, and neurobiological deficits that can range in their severity. Despite extensive research in the field and a significant progress made, especially in understanding the range of possible malformations and neurobehavioral abnormalities, the molecular mechanisms of alcohol responses in development are still not well understood. There have been multiple transcriptomic studies looking at the changes in gene expression after PAE in animal models; however, there is a limited apparent consensus among the reported findings. In an effort to address this issue, we performed a comprehensive re-analysis and meta-analysis of all suitable, publically available expression data sets. METHODS: We assembled 10 microarray data sets of gene expression after PAE in mouse and rat models consisting of samples from a total of 63 ethanol (EtOH)-exposed and 80 control animals. We re-analyzed each data set for differential expression and then used the results to perform meta-analyses considering all data sets together or grouping them by time or duration of exposure (pre- and postnatal, acute and chronic, respectively). We performed network and Gene Ontology enrichment analysis to further characterize the identified signatures. RESULTS: For each subanalysis, we identified signatures of differential expressed genes that show support from multiple studies. Overall, the changes in gene expression were more extensive after acute EtOH treatment during prenatal development than in other models. Considering the analysis of all the data together, we identified a robust core signature of 104 genes down-regulated after PAE, with no up-regulated genes. Functional analysis reveals over representation of genes involved in protein synthesis, mRNA splicing, and chromatin organization. CONCLUSIONS: Our meta-analysis shows that existing studies, despite superficial dissimilarity in findings, share features that allow us to identify a common core signature set of transcriptome changes in PAE. This is an important step to identifying the biological processes that underlie the etiology of fetal alcohol spectrum disorders.


Asunto(s)
Ensamble y Desensamble de Cromatina/fisiología , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica/fisiología , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Biosíntesis de Proteínas/fisiología , Animales , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Etanol/administración & dosificación , Etanol/toxicidad , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Ratones , Embarazo , Biosíntesis de Proteínas/efectos de los fármacos , Ratas
9.
Blood ; 121(16): 3161-4, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23407552

RESUMEN

We have recently reported the application of RNAseq to mantle cell lymphoma (MCL) transcriptomes revealing recurrent mutations in NOTCH1. Here we describe the targeted resequencing of 18 genes mutated in this discovery cohort using a larger cohort of MCL tumors. In addition to frequent mutations in ATM, CCND1, TP53, and NOTCH1, mutations were also observed recurrently in MEF2B, TRAF2, and TET2. Interestingly, the third most frequently mutated gene was UBR5, a gene encoding a 2799aa protein, with multiple functions, including E3 ligase activity based on a conserved cysteine residue at the C-terminus. Nonsynonymous mutations were detected in 18% (18/102) of tumors, with 61% of the mutations resulting in frameshifts in, or around, exon 58, predicted to result in the loss of this conserved cysteine residue. The recurrence and clustering of deleterious mutations implicate UBR5 mutations as a critical pathogenic event in a subgroup of MCL.


Asunto(s)
Linfoma de Células del Manto/genética , Mutación , Ubiquitina-Proteína Ligasas/genética , Secuencia de Aminoácidos , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Estudios de Cohortes , Ciclina D1/genética , Proteínas de Unión al ADN/genética , Humanos , Linfoma de Células del Manto/química , Datos de Secuencia Molecular , Proteínas Serina-Treonina Quinasas/genética , Receptor Notch1/genética , Alineación de Secuencia , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética
10.
Blood ; 122(7): 1256-65, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23699601

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer composed of at least 2 molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease. Here we provide a whole-genome-sequencing-based perspective of DLBCL mutational complexity by characterizing 40 de novo DLBCL cases and 13 DLBCL cell lines and combining these data with DNA copy number analysis and RNA-seq from an extended cohort of 96 cases. Our analysis identified widespread genomic rearrangements including evidence for chromothripsis as well as the presence of known and novel fusion transcripts. We uncovered new gene targets of recurrent somatic point mutations and genes that are targeted by focal somatic deletions in this disease. We highlight the recurrence of germinal center B-cell-restricted mutations affecting genes that encode the S1P receptor and 2 small GTPases (GNA13 and GNAI2) that together converge on regulation of B-cell homing. We further analyzed our data to approximate the relative temporal order in which some recurrent mutations were acquired and demonstrate that ongoing acquisition of mutations and intratumoral clonal heterogeneity are common features of DLBCL. This study further improves our understanding of the processes and pathways involved in lymphomagenesis, and some of the pathways mutated here may indicate new avenues for therapeutic intervention.


Asunto(s)
Biomarcadores de Tumor/química , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN/genética , Genoma Humano , Linfoma de Células B Grandes Difuso/genética , Mutación/genética , Subunidades alfa de la Proteína de Unión al GTP G12-G13/química , Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
11.
Blood ; 119(9): 1963-71, 2012 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-22210878

RESUMEN

Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.


Asunto(s)
Linfoma de Células del Manto/genética , Mutación , Receptor Notch1/genética , Análisis de Secuencia de ARN , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Bases , Benzodiazepinonas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina D1/genética , Exones , Femenino , Perfilación de la Expresión Génica , Humanos , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Receptor Notch1/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia
12.
Blood ; 119(21): 4949-52, 2012 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-22496164

RESUMEN

Recently, the landscape of single base mutations in diffuse large B-cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal center B cell-like (GCB) DLBCL is 5% (6 of 115). The fusion appears exclusive to GCB and was not seen in 138 non-GCB cases examined (P = .008, Fisher exact test) but was present at low incidence in follicular lymphoma (1 of 81). In all 7 cases identified, the 3' end of the fusion consists of exons 4 and onwards of TP63. The recurrence, subtype enrichment, and the remarkably conserved nature of the TP63 portion of the fusion suggest an important functional role in the lymphomas that harbor this event.


Asunto(s)
Linfoma de Células B/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Secuencia de Bases , Cromosomas Humanos Par 3/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Hibridación Fluorescente in Situ , Incidencia , Linfoma de Células B/epidemiología , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Datos de Secuencia Molecular
13.
Artículo en Inglés | MEDLINE | ID: mdl-37918557

RESUMEN

OBJECTIVE: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia. METHODS: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described. RESULTS: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations. CONCLUSIONS: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.


Asunto(s)
Discapacidad Intelectual , Trastornos Psicóticos , Esquizofrenia , Humanos , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Fenotipo , Trastornos Psicóticos/genética , Trastornos Psicóticos/psicología , Esquizofrenia/genética
14.
Nat Commun ; 11(1): 2073, 2020 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-32350270

RESUMEN

Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.


Asunto(s)
Enfermedad/genética , Modelos Genéticos , Mutación Missense/genética , Fosfohidrolasa PTEN/genética , Animales , Conducta Animal , Caenorhabditis elegans/fisiología , Células Cultivadas , Dendritas/fisiología , Drosophila/genética , Drosophila/crecimiento & desarrollo , Pruebas de Enzimas , Células HEK293 , Humanos , Neoplasias/genética , Sistema Nervioso/crecimiento & desarrollo , Fosforilación , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Piramidales/metabolismo , Ratas Sprague-Dawley , Saccharomyces cerevisiae/metabolismo
15.
Autism Res ; 12(12): 1728-1736, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31705629

RESUMEN

Recent years have seen a boom in the application of the next-generation sequencing technology to the study of human disorders, including Autism Spectrum Disorder (ASD), where the focus has been on identifying rare, possibly causative genomic variants in ASD individuals. Because of the high genetic heterogeneity of ASD, a large number of subjects is needed to establish evidence for a variant or gene ASD-association, thus aggregating data across cohorts and studies is necessary. However, methodological inconsistencies and subject overlap across studies complicate data aggregation. Here we present VariCarta, a web-based database developed to address these challenges by collecting, reconciling, and consistently cataloging literature-derived genomic variants found in ASD subjects using ongoing semi-manual curation. The careful manual curation combined with a robust data import pipeline rectifies errors, converts variants into a standardized format, identifies and harmonizes cohort overlaps, and documents data provenance. The harmonization aspect is especially important since it prevents the potential double counting of variants, which can lead to inflation of gene-based evidence for ASD-association. The database currently contains 170,416 variant events from 10,893 subjects, collected across 61 publications, and reconciles 16,202 variants that have been reported in literature multiple times. VariCarta is freely accessible at http://varicarta.msl.ubc.ca. Autism Res 2019, 12: 1728-1736. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The search for genetic factors underlying Autism Spectrum Disorder (ASD) yielded numerous studies reporting potentially causative genomic variants found in ASD individuals. However, methodological differences and subject overlap across studies complicate the assembly of these data, diminishing its utility and accessibility. We developed VariCarta, a web-based database that aggregates carefully curated, annotated, and harmonized literature-derived variants identified in individuals with ASD using ongoing semi-manual curation.


Asunto(s)
Trastorno del Espectro Autista/genética , Bases de Datos Genéticas/estadística & datos numéricos , Femenino , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino
16.
BMC Genomics ; 9: 355, 2008 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-18664289

RESUMEN

BACKGROUND: Secondary structure interactions within introns have been shown to be essential for efficient splicing of several yeast genes. The nature of these base-pairing interactions and their effect on splicing efficiency were most extensively studied in ribosomal protein gene RPS17B (previously known as RP51B). It was determined that complementary pairing between two sequence segments located downstream of the 5' splice site and upstream of the branchpoint sequence promotes efficient splicing of the RPS17B pre-mRNA, presumably by shortening the branchpoint distance. However, no attempts were made to compute a shortened, 'structural' branchpoint distance and thus the functional relationship between this distance and the splicing efficiency remains unknown. RESULTS: In this paper we use computational RNA secondary structure prediction to analyze the secondary structure of the RPS17B intron. We show that it is necessary to consider suboptimal structure predictions and to compute the structural branchpoint distances in order to explain previously published splicing efficiency results. Our study reveals that there is a tight correlation between this distance and splicing efficiency levels of intron mutants described in the literature. We experimentally test this correlation on additional RPS17B mutants and intron mutants within two other yeast genes. CONCLUSION: The proposed model of secondary structure requirements for efficient splicing is the first attempt to specify the functional relationship between pre-mRNA secondary structure and splicing. Our findings provide further insights into the role of pre-mRNA secondary structure in gene splicing in yeast and also offer basis for improvement of computational methods for splice site identification and gene-finding.


Asunto(s)
Intrones , Precursores del ARN/genética , Empalme del ARN , ARN Mensajero/genética , Saccharomyces cerevisiae/genética , Algoritmos , Emparejamiento Base , Biología Computacional , Genes Fúngicos , Genoma Fúngico , Mutación , Conformación de Ácido Nucleico , ARN de Hongos/genética , Proteínas Ribosómicas/genética , Proteínas de Saccharomyces cerevisiae/genética
17.
Autism Res ; 8(5): 593-608, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25720351

RESUMEN

Autism spectrum disorders (ASD) are clinically heterogeneous and biologically complex. In general it remains unclear, what biological factors lead to changes in the brains of autistic individuals. A considerable number of transcriptome analyses have been performed in attempts to address this question, but their findings lack a clear consensus. As a result, each of these individual studies has not led to any significant advance in understanding the autistic phenotype as a whole. Here, we report a meta-analysis of more than 1000 microarrays across twelve independent studies on expression changes in ASD compared to unaffected individuals, in both blood and brain tissues. We identified a number of known and novel genes that are consistently differentially expressed across three studies of the brain (71 samples in total). A subset of the highly ranked genes is suggestive of effects on mitochondrial function. In blood, consistent changes were more difficult to identify, despite individual studies tending to exhibit larger effects than the brain studies. Our results are the strongest evidence to date of a common transcriptome signature in the brains of individuals with ASD.


Asunto(s)
Trastorno del Espectro Autista/genética , Expresión Génica/genética , Humanos , Análisis por Micromatrices/estadística & datos numéricos
18.
Am J Psychiatry ; 172(11): 1131-40, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26238605

RESUMEN

OBJECTIVE: Gene expression dysregulation in the brain has been associated with bipolar disorder through candidate gene and microarray expression studies, but questions remain about isoform-specific dysregulation and the role of noncoding RNAs whose importance in the brain has been suggested recently but not yet characterized for bipolar disorder. METHOD: The authors used RNA sequencing, a powerful technique that captures the complexity of gene expression, in postmortem tissue from the anterior cingulate cortex from 13 bipolar disorder case subjects and 13 matched comparison subjects. Differential expression was computed, and a global pattern of downregulation was detected, with 10 transcripts significant at a false discovery rate ≤5%. Importantly, all 10 genes were also replicated in an independent RNA sequencing data set (N=61) from the anterior cingulate cortex. RESULTS: Among the most significant results were genes coding for class A G protein-coupled receptors: SSTR2 (somatostatin receptor 2), CHRM2 (cholinergic receptor, muscarinic 2), and RXFP1 (relaxin/insulin-like family peptide receptor 1). A gene ontology analysis of the entire set of differentially expressed genes pointed to an overrepresentation of genes involved in G protein-coupled receptor regulation. The top genes were followed up by querying the effect of treatment with mood stabilizers commonly prescribed in bipolar disorder, which showed that these drugs modulate expression of the candidate genes. CONCLUSIONS: By using RNA sequencing in the postmortem bipolar disorder brain, an interesting profile of G protein-coupled receptor dysregulation was identified, several new bipolar disorder genes were indicated, and the noncoding transcriptome in bipolar disorder was characterized. These findings have important implications with regard to fine-tuning our understanding of the bipolar disorder brain, as well as for identifying potential new drug target pathways.


Asunto(s)
Trastorno Bipolar/genética , Regulación de la Expresión Génica/genética , Giro del Cíngulo/metabolismo , ARN Mensajero/metabolismo , Receptor Muscarínico M2/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genética , Receptores de Somatostatina/genética , Adulto , Antimaníacos/farmacología , Trastorno Bipolar/metabolismo , Carbamazepina/farmacología , Estudios de Casos y Controles , Línea Celular , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Compuestos de Litio/farmacología , Masculino , Persona de Mediana Edad , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , ARN Mensajero/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Muscarínico M2/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores de Péptidos/efectos de los fármacos , Receptores de Somatostatina/efectos de los fármacos , Análisis de Secuencia de ARN , Ácido Valproico/farmacología
19.
Nat Genet ; 46(4): 329-35, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24531327

RESUMEN

Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.


Asunto(s)
Enfermedad de Hodgkin/genética , Linfoma de Células B/genética , Neoplasias del Mediastino/genética , Mutación/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Perfilación de la Expresión Génica/métodos , Técnicas de Silenciamiento del Gen , Genómica/métodos , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento , Enfermedad de Hodgkin/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Captura por Microdisección con Láser , Linfoma de Células B/patología , Neoplasias del Mediastino/patología , Fosforilación , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa
20.
J Clin Oncol ; 31(6): 692-700, 2013 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-23182984

RESUMEN

PURPOSE: Our aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET). METHODS: Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry. RESULTS: A 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses. CONCLUSION: A gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Perfilación de la Expresión Génica/métodos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/genética , Análisis de Matrices Tisulares/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Fijadores , Formaldehído , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adhesión en Parafina , Pronóstico , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Análisis de Supervivencia , Adulto Joven
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