Dataset Information

Mouse Genetic Models of Human Brain Disorders.

ABSTRACT: Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases.

SUBMITTER: Leung C

PROVIDER: S-EPMC4803727 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Mouse Genetic Models of Human Brain Disorders.

Leung Celeste C Jia Zhengping Z

Frontiers in genetics 20160323

Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual d ...[more]

PMID: 27047540

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Project description:The 2019 International Skeletal Dysplasia Society nosology update lists 441 genes for which mutations result in rare human skeletal disorders. These genes code for enzymes (33%), scaffolding proteins (18%), signal transduction proteins (16%), transcription factors (14%), cilia proteins (8%), extracellular matrix proteins (5%), and membrane transporters (4%). Skeletal disorders include aggrecanopathies, channelopathies, ciliopathies, cohesinopathies, laminopathies, linkeropathies, lysosomal storage diseases, protein-folding and RNA splicing defects, and ribosomopathies. With the goal of evaluating the ability of mouse models to mimic these human genetic skeletal disorders, a PubMed literature search identified 260 genes for which mutant mice were examined for skeletal phenotypes. These mouse models included spontaneous and ENU-induced mutants, global and conditional gene knockouts, and transgenic mice with gene over-expression or specific base-pair substitutions. The human X-linked gene ARSE and small nuclear RNA U4ATAC, a component of the minor spliceosome, do not have mouse homologs. Mouse skeletal phenotypes mimicking human skeletal disorders were observed in 249 of the 260 genes (96%) for which comparisons are possible. A supplemental table in spreadsheet format provides PubMed weblinks to representative publications of mutant mouse skeletal phenotypes. Mutations in 11 mouse genes (Ccn6, Cyp2r1, Flna, Galns, Gna13, Lemd3, Manba, Mnx1, Nsd1, Plod1, Smarcal1) do not result in similar skeletal phenotypes observed with mutations of the homologous human genes. These discrepancies can result from failure of mouse models to mimic the exact human gene mutations. There are no obvious commonalities among these 11 genes. Body BMD and/or radiologic dysmorphology phenotypes were successfully identified for 28 genes by the International Mouse Phenotyping Consortium (IMPC). Forward genetics using ENU mouse mutagenesis successfully identified 37 nosology gene phenotypes. Since many human genetic disorders involve hypomorphic, gain-of-function, dominant-negative and intronic mutations, future studies will undoubtedly utilize CRISPR/Cas9 technology to examine transgenic mice having genes modified to exactly mimic variant human sequences. Mutant mice will increasingly be employed for drug development studies designed to treat human genetic skeletal disorders.SignificanceGreat progress is being made identifying mutant genes responsible for human rare genetic skeletal disorders and mouse models for genes affecting bone mass, architecture, mineralization and strength. This review organizes data for 441 human genetic bone disorders with regard to heredity, gene function, molecular pathways, and fidelity of relevant mouse models to mimic the human skeletal disorders. PubMed weblinks to citations of 249 successful mouse models are provided.

Dataset Information

Mouse Genetic Models of Human Brain Disorders.

Publications

Mouse Genetic Models of Human Brain Disorders.

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