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Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.
Pubmed ID: 29100091
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Project aggregates and provides experimental gene expression data from genito-urinary system. International consortium providing molecular atlas of gene expression for developing organs of GenitoUrinary (GU) tract. Mouse strains to facilitate developmental and functional studies within GU system. Experimental protocols and standard specifications. Tutorials describing GU organogenesis and primary data via database. Data are from large-scale in situ hybridization screens (wholemount and section) and microarray gene expression data of microdissected, laser-captured and FACS-sorted components of developing mouse genitourinary (GU) system.
View all literature mentionsCollection of data of protein sequence and functional information. Resource for protein sequence and annotation data. Consortium for preservation of the UniProt databases: UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc), UniProt Proteomes. Collaboration between European Bioinformatics Institute (EMBL-EBI), SIB Swiss Institute of Bioinformatics and Protein Information Resource. Swiss-Prot is a curated subset of UniProtKB.
View all literature mentionsDatabase of human genes that provides concise genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. Information featured in GeneCards includes orthologies, disease relationships, mutations and SNPs, gene expression, gene function, pathways, protein-protein interactions, related drugs and compounds and direct links to cutting edge research reagents and tools such as antibodies, recombinant proteins, clones, expression assays and RNAi reagents.
View all literature mentionsOnline catalog of human genes and genetic disorders, for clinical features, phenotypes and genes. Collection of human genes and genetic phenotypes, focusing on relationship between phenotype and genotype. Referenced overviews in OMIM contain information on all known mendelian disorders and variety of related genes. It is updated daily, and entries contain copious links to other genetics resources.
View all literature mentionsInternational database for laboratory mouse. Data offered by The Jackson Laboratory includes information on integrated genetic, genomic, and biological data. MGI creates and maintains integrated representation of mouse genetic, genomic, expression, and phenotype data and develops reference data set and consensus data views, synthesizes comparative genomic data between mouse and other mammals, maintains set of links and collaborations with other bioinformatics resources, develops and supports analysis and data submission tools, and provides technical support for database users. Projects contributing to this resource are: Mouse Genome Database (MGD) Project, Gene Expression Database (GXD) Project, Mouse Tumor Biology (MTB) Database Project, Gene Ontology (GO) Project at MGI, and MouseCyc Project at MGI.
View all literature mentionsDetailed multidimensional digital multimodal atlas of C57BL/6J mouse nervous system with data and informatics pipeline that can automatically register, annotate, and visualize large scale neuroanatomical and connectivity data produced in histology, neuronal tract tracing, MR imaging, and genetic labeling. MAP2.0 interoperates with commonly used publicly available databases to bring together brain architecture, gene expression, and imaging information into single, simple interface.Resource to visualise mouse development, identify anatomical structures, determine developmental stage, and investigate gene expression in mouse embryo. eMouseAtlas portal page allows access to EMA Anatomy Atlas of Mouse Development and EMAGE database of gene expression.EMAGE is freely available, curated database of gene expression patterns generated by in situ techniques in developing mouse embryo. EMA, e-Mouse Atlas, is 3-D anatomical atlas of mouse embryo development including histology and includes EMAP ontology of anatomical structure, provides information about shape, gross anatomy and detailed histological structure of mouse, and framework into which information about gene function can be mapped.
View all literature mentionsData analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsSoftware tool which predicts possible impact of amino acid substitution on structure and function of human protein using straightforward physical and comparative considerations. PolyPhen-2 is new development of PolyPhen tool for annotating coding nonsynonymous SNPs.
View all literature mentionsDatabase that aggregates exome and genome sequencing data from large-scale sequencing projects. The gnomAD data set contains individuals sequenced using multiple exome capture methods and sequencing chemistries. Raw data from the projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects.
View all literature mentionsWeb application that helps design, evaluate and clone guide sequences for the CRISPR/Cas9 system. This sgRNA design tool assists with guide selection in a variety of genomes and pre-calculated results for all human coding exons as a UCSC Genome Browser track.
View all literature mentionsDetailed multidimensional digital multimodal atlas of C57BL/6J mouse nervous system with data and informatics pipeline that can automatically register, annotate, and visualize large scale neuroanatomical and connectivity data produced in histology, neuronal tract tracing, MR imaging, and genetic labeling. MAP2.0 interoperates with commonly used publicly available databases to bring together brain architecture, gene expression, and imaging information into single, simple interface.Resource to visualise mouse development, identify anatomical structures, determine developmental stage, and investigate gene expression in mouse embryo. eMouseAtlas portal page allows access to EMA Anatomy Atlas of Mouse Development and EMAGE database of gene expression.EMAGE is freely available, curated database of gene expression patterns generated by in situ techniques in developing mouse embryo. EMA, e-Mouse Atlas, is 3-D anatomical atlas of mouse embryo development including histology and includes EMAP ontology of anatomical structure, provides information about shape, gross anatomy and detailed histological structure of mouse, and framework into which information about gene function can be mapped.
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The NIDDK Information Network (dkNET) serves the needs of basic and clinical investigators by providing seamless access to large pools of data and research resources relevant to the mission of The National Institute of Diabetes Digestive and Kidney Diseases (NIDDK). dkNET is hosted at University of California San Diego, and is supported by NIH NIDDK grant U24DK097771.
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