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1.
Cell ; 169(1): 6-12, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28340351

RESUMO

Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.


Assuntos
Pesquisa Biomédica , Genômica , Animais , Análise Mutacional de DNA , Bases de Dados Genéticas , Doença/genética , Projeto Genoma Humano , Humanos , Disseminação de Informação , Modelos Animais
3.
Am J Hum Genet ; 107(6): 1096-1112, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33232675

RESUMO

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.


Assuntos
Proteínas Cromossômicas não Histona/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Fenótipo , Proteínas Supressoras de Tumor/genética , Adolescente , Animais , Criança , Pré-Escolar , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Genes Dominantes , Variação Genética , Haploinsuficiência , Humanos , Lactente , Masculino , Microscopia Confocal , Neuroglia/metabolismo , Neurônios/metabolismo , Ligação Proteica , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
4.
Nucleic Acids Res ; 49(D1): D1058-D1064, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33170210

RESUMO

The Zebrafish Information Network (ZFIN) (https://zfin.org/) is the database for the model organism, zebrafish (Danio rerio). ZFIN expertly curates, organizes, and provides a wide array of zebrafish genetic and genomic data, including genes, alleles, transgenic lines, gene expression, gene function, mutant phenotypes, orthology, human disease models, gene and mutant nomenclature, and reagents. New features at ZFIN include major updates to the home page and the gene page, the two most used pages at ZFIN. Data including disease models, phenotypes, expression, mutants and gene function continue to be contributed to The Alliance of Genome Resources for integration with similar data from other model organisms.


Assuntos
Biologia Computacional/métodos , Bases de Dados Genéticas , Genoma/genética , Genômica/métodos , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Mineração de Dados/métodos , Expressão Gênica , Humanos , Internet , Modelos Animais , Mutação , Fenótipo , Proteínas de Peixe-Zebra/genética
6.
PLoS Genet ; 16(6): e1008841, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544203

RESUMO

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Bainha de Mielina/patologia , Neurogênese/genética , Proteínas Supressoras de Tumor/genética , Animais , Plexo Braquial/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Mutação da Fase de Leitura , Substância Cinzenta/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Imageamento por Ressonância Magnética , Neuroglia/patologia , Oligodendroglia , Nervo Isquiático/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Sequenciamento do Exoma , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
7.
Am J Hum Genet ; 104(3): 422-438, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773277

RESUMO

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.


Assuntos
Instabilidade Cromossômica , Dano ao DNA , Variação Genética , Anormalidades Musculoesqueléticas/patologia , NF-kappa B/genética , Osteocondrodisplasias/patologia , Adolescente , Adulto , Alelos , Animais , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Estudos de Associação Genética , Humanos , Camundongos , Camundongos Knockout , Anormalidades Musculoesqueléticas/genética , Osteocondrodisplasias/genética , Sequenciamento do Exoma , Adulto Jovem , Peixe-Zebra
8.
N Engl J Med ; 379(22): 2131-2139, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30304647

RESUMO

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).


Assuntos
Testes Genéticos , Doenças Raras/genética , Análise de Sequência de DNA , Adulto , Animais , Criança , Diagnóstico Diferencial , Drosophila , Exoma , Feminino , Testes Genéticos/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Masculino , Modelos Animais , National Institutes of Health (U.S.) , Doenças Raras/diagnóstico , Síndrome , Estados Unidos
9.
Genet Med ; 23(10): 1889-1900, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34113007

RESUMO

PURPOSE: Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. METHODS: We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. RESULTS: Patients with variants in GDF11 presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients' variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants in our cohort are partial LOF variants. CONCLUSION: GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.


Assuntos
Proteínas Morfogenéticas Ósseas , Anormalidades Craniofaciais/genética , Fatores de Diferenciação de Crescimento , Animais , Proteínas Morfogenéticas Ósseas/genética , Fatores de Diferenciação de Crescimento/genética , Humanos , Mutação de Sentido Incorreto , Fenótipo , Coluna Vertebral , Peixe-Zebra/genética
10.
Nucleic Acids Res ; 47(D1): D867-D873, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407545

RESUMO

The Zebrafish Information Network (ZFIN) (https://zfin.org/) is the database for the model organism, zebrafish (Danio rerio). ZFIN expertly curates, organizes and provides a wide array of zebrafish genetic and genomic data, including genes, alleles, transgenic lines, gene expression, gene function, mutant phenotypes, orthology, human disease models, nomenclature and reagents. New features at ZFIN include increased support for genomic regions and for non-coding genes, and support for more expressive Gene Ontology annotations. ZFIN has recently taken over maintenance of the zebrafish reference genome sequence as part of the Genome Reference Consortium. ZFIN is also a founding member of the Alliance of Genome Resources, a collaboration of six model organism databases (MODs) and the Gene Ontology Consortium (GO). The recently launched Alliance portal (https://alliancegenome.org) provides a unified, comparative view of MOD, GO, and human data, and facilitates foundational and translational biomedical research.


Assuntos
Bases de Dados Genéticas , Genoma/genética , Genômica , Peixe-Zebra/genética , Animais , Expressão Gênica/genética , Ontologia Genética , Humanos , Anotação de Sequência Molecular , Mutação/genética , Fenótipo
11.
Nucleic Acids Res ; 45(D1): D758-D768, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-27899582

RESUMO

The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, 'Fish' records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search.


Assuntos
Bases de Dados Genéticas , Estudos de Associação Genética/métodos , Genômica/métodos , Ferramenta de Busca , Peixe-Zebra/genética , Animais , Biologia Computacional/métodos , Curadoria de Dados , Modelos Animais de Doenças , Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , Fenótipo
12.
PLoS Genet ; 12(5): e1006054, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27195754

RESUMO

Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.


Assuntos
Proteínas de Drosophila/genética , Olho/metabolismo , Cinesinas/genética , Ubiquitina-Proteína Ligases/genética , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Proteínas Hedgehog/genética , Cinesinas/metabolismo , Camundongos , Células Fotorreceptoras/metabolismo , Poliubiquitina , Proteólise , RNA Interferente Pequeno , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Peixe-Zebra/genética
13.
Exp Eye Res ; 173: 148-159, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29777677

RESUMO

Mutations in USH2A are the most frequent cause of Usher syndrome and autosomal recessive nonsyndromic retinitis pigmentosa. To unravel the pathogenic mechanisms underlying USH2A-associated retinal degeneration and to evaluate future therapeutic strategies that could potentially halt the progression of this devastating disorder, an animal model is needed. The available Ush2a knock-out mouse model does not mimic the human phenotype, because it presents with only a mild and late-onset retinal degeneration. Using CRISPR/Cas9-technology, we introduced protein-truncating germline lesions into the zebrafish ush2a gene (ush2armc1: c.2337_2342delinsAC; p.Cys780GlnfsTer32 and ush2ab1245: c.15520_15523delinsTG; p.Ala5174fsTer). Homozygous mutants were viable and displayed no obvious morphological or developmental defects. Immunohistochemical analyses with antibodies recognizing the N- or C-terminal region of the ush2a-encoded protein, usherin, demonstrated complete absence of usherin in photoreceptors of ush2armc1, but presence of the ectodomain of usherin at the periciliary membrane of ush2ab1245-derived photoreceptors. Furthermore, defects of usherin led to a reduction in localization of USH2 complex members, whirlin and Adgrv1, at the photoreceptor periciliary membrane of both mutants. Significantly elevated levels of apoptotic photoreceptors could be observed in both mutants when kept under constant bright illumination for three days. Electroretinogram (ERG) recordings revealed a significant and similar decrease in both a- and b-wave amplitudes in ush2armc1 as well as ush2ab1245 larvae as compared to strain- and age-matched wild-type larvae. In conclusion, this study shows that mutant ush2a zebrafish models present with early-onset retinal dysfunction that is exacerbated by light exposure. These models provide a better understanding of the pathophysiology underlying USH2A-associated RP and a unique opportunity to evaluate future therapeutic strategies.


Assuntos
Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Degeneração Retiniana/genética , Síndromes de Usher/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra , Animais , Apoptose , Eletrorretinografia , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/fisiologia , Técnicas de Inativação de Genes , Técnicas de Genotipagem , Proteínas de Membrana/metabolismo , Microscopia Imunoeletrônica , Mutação , Retina/fisiopatologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/fisiopatologia , Segmento Externo das Células Fotorreceptoras da Retina/metabolismo , Segmento Externo das Células Fotorreceptoras da Retina/ultraestrutura , Receptor do Retrovírus Politrópico e Xenotrópico , Proteínas de Peixe-Zebra/metabolismo
14.
Mol Biol Evol ; 33(1): 13-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26500251

RESUMO

Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology.


Assuntos
Peixes-Gato/genética , Evolução Molecular , Expressão Gênica , Modelos Genéticos , Fenótipo , Animais , Biologia Computacional , Expressão Gênica/genética , Expressão Gênica/fisiologia , Software
15.
Hum Mol Genet ; 24(9): 2594-603, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25616960

RESUMO

Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066*, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066* as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs*16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984* identified by preconception screening ('Kingsmore panel') do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screening.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Estudos de Associação Genética , Mutação , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transporte Vesicular , Animais , Encéfalo/patologia , Cerebelo/anormalidades , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Modelos Animais de Doenças , Evolução Molecular , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Ordem dos Genes , Genes Recessivos , Loci Gênicos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Linhagem , Conformação Proteica , Retina/anormalidades , Peixe-Zebra/genética
16.
Nucleic Acids Res ; 42(Database issue): D966-74, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24217912

RESUMO

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.


Assuntos
Ontologias Biológicas , Bases de Dados Factuais , Doenças Genéticas Inatas/genética , Fenótipo , Animais , Doenças Genéticas Inatas/diagnóstico , Genômica , Humanos , Internet , Camundongos
17.
Genesis ; 53(8): 498-509, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26097180

RESUMO

The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for genetic and genomic data from zebrafish (Danio rerio) research. ZFIN staff curate detailed information about genes, mutants, genotypes, reporter lines, sequences, constructs, antibodies, knockdown reagents, expression patterns, phenotypes, gene product function, and orthology from publications. Researchers can submit mutant, transgenic, expression, and phenotype data directly to ZFIN and use the ZFIN Community Wiki to share antibody and protocol information. Data can be accessed through topic-specific searches, a new site-wide search, and the data-mining resource ZebrafishMine (http://zebrafishmine.org). Data download and web service options are also available. ZFIN collaborates with major bioinformatics organizations to verify and integrate genomic sequence data, provide nomenclature support, establish reciprocal links, and participate in the development of standardized structured vocabularies (ontologies) used for data annotation and searching. ZFIN-curated gene, function, expression, and phenotype data are available for comparative exploration at several multi-species resources. The use of zebrafish as a model for human disease is increasing. ZFIN is supporting this growing area with three major projects: adding easy access to computed orthology data from gene pages, curating details of the gene expression pattern changes in mutant fish, and curating zebrafish models of human diseases.


Assuntos
Bases de Dados Genéticas , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Biologia Computacional/métodos , Curadoria de Dados/métodos , Estudos de Associação Genética , Genômica/métodos , Internet , Modelos Animais
18.
Genesis ; 53(8): 547-60, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26097192

RESUMO

InterMine is a data integration warehouse and analysis software system developed for large and complex biological data sets. Designed for integrative analysis, it can be accessed through a user-friendly web interface. For bioinformaticians, extensive web services as well as programming interfaces for most common scripting languages support access to all features. The web interface includes a useful identifier look-up system, and both simple and sophisticated search options. Interactive results tables enable exploration, and data can be filtered, summarized, and browsed. A set of graphical analysis tools provide a rich environment for data exploration including statistical enrichment of sets of genes or other entities. InterMine databases have been developed for the major model organisms, budding yeast, nematode worm, fruit fly, zebrafish, mouse, and rat together with a newly developed human database. Here, we describe how this has facilitated interoperation and development of cross-organism analysis tools and reports. InterMine as a data exploration and analysis tool is also described. All the InterMine-based systems described in this article are resources freely available to the scientific community.


Assuntos
Bases de Dados Factuais , Software , Animais , Biologia Computacional/métodos , Bases de Dados Genéticas , Genômica , Humanos , Internet , Integração de Sistemas , Interface Usuário-Computador
19.
Nucleic Acids Res ; 41(Database issue): D854-60, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23074187

RESUMO

ZFIN, the Zebrafish Model Organism Database (http://zfin.org), is the central resource for zebrafish genetic, genomic, phenotypic and developmental data. ZFIN curators manually curate and integrate comprehensive data involving zebrafish genes, mutants, transgenics, phenotypes, genotypes, gene expressions, morpholinos, antibodies, anatomical structures and publications. Integrated views of these data, as well as data gathered through collaborations and data exchanges, are provided through a wide selection of web-based search forms. Among the vertebrate model organisms, zebrafish are uniquely well suited for rapid and targeted generation of mutant lines. The recent rapid production of mutants and transgenic zebrafish is making management of data associated with these resources particularly important to the research community. Here, we describe recent enhancements to ZFIN aimed at improving our support for mutant and transgenic lines, including (i) enhanced mutant/transgenic search functionality; (ii) more expressive phenotype curation methods; (iii) new downloads files and archival data access; (iv) incorporation of new data loads from laboratories undertaking large-scale generation of mutant or transgenic lines and (v) new GBrowse tracks for transgenic insertions, genes with antibodies and morpholinos.


Assuntos
Bases de Dados Genéticas , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Genômica , Internet , Modelos Animais , Mutação , Fenótipo
20.
Hum Mutat ; 35(10): 1153-62, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25044745

RESUMO

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.


Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Proteínas de Ciclo Celular/metabolismo , Doenças Cerebelares/metabolismo , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Cílios/metabolismo , Cílios/ultraestrutura , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Técnicas de Silenciamento de Genes , Humanos , Iraque , Rim/patologia , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Retina/metabolismo , Retina/patologia , Peixe-Zebra
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