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1.
Dev Dyn ; 250(10): 1463-1476, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33715275

RESUMO

BACKGROUND: Orofacial clefts (OFCs) are common birth defects with complex etiology. Genome wide association studies for OFC have identified SNPs in and near MAFB. MAFB is a transcription factor critical for structural development of digits, kidneys, skin, and brain. MAFB is also expressed in the craniofacial region. Previous sequencing of MAFB in a Filipino population revealed a novel missense variant significantly associated with an increased risk for OFC. This MAFB variant, leading to the amino acid change H131Q, was knocked into the mouse Mafb, resulting in the MafbH131Q allele. The MafbH131Q construct was engineered to allow for deletion of Mafb ("Mafbdel "). RESULTS: Mafbdel/del animals died shortly after birth. Conversely, MafbH131Q/H131Q mice survived into adulthood at Mendelian ratios. Mafbdel/del and MafbH131Q/H131Q heads exhibited normal macroscopic and histological appearance at all embryonic time points evaluated. The periderm was intact based on expression of keratin 6, p63, and E-cadherin. Despite no effect on craniofacial morphogenesis, H131Q inhibited the Mafb-dependent promoter activation of Arhgap29 in palatal mesenchymal, but not ectodermal-derived epithelial cells in a luciferase assay. CONCLUSIONS: Mafb is dispensable for murine palatogenesis in vivo, and the cleft-associated variant H131Q, despite its lack of morphogenic effect, altered the expression of Arhgap29 in a cell-dependent context.


Assuntos
Fissura Palatina/metabolismo , Fator de Transcrição MafB/metabolismo , Palato/metabolismo , Polimorfismo de Nucleotídeo Único , Alelos , Animais , Fissura Palatina/genética , Predisposição Genética para Doença , Fator de Transcrição MafB/genética , Camundongos , Camundongos Transgênicos , Palato/embriologia
2.
Genome Res ; 25(7): 948-57, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25917818

RESUMO

Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.


Assuntos
Exoma , Mutação , Animais , Feminino , Doenças Genéticas Inatas/genética , Ligação Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Fenótipo , Reprodutibilidade dos Testes
3.
Sci Rep ; 11(1): 18168, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518579

RESUMO

TAR DNA-binding protein-43 (TDP-43) is known to accumulate in ubiquitinated inclusions of amyotrophic lateral sclerosis affected motor neurons, resulting in motor neuron degeneration, loss of motor functions, and eventually death. Rapamycin, an mTOR inhibitor and a commonly used immunosuppressive drug, has been shown to increase the survivability of Amyotrophic Lateral Sclerosis (ALS) affected motor neurons. Here we present a transgenic, TDP-43-A315T, mouse model expressing an ALS phenotype and demonstrate the presence of ubiquitinated cytoplasmic TDP-43 aggregates with > 80% cell death by 28 days post differentiation in vitro. Embryonic stem cells from this mouse model were used to study the onset, progression, and therapeutic remediation of TDP-43 aggregates using a novel microfluidic rapamycin concentration gradient generator. Results using a microfluidic device show that ALS affected motor neuron survival can be increased by 40.44% in a rapamycin dosage range between 0.4-1.0 µM.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Microfluídica , Neurônios Motores/patologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Sirolimo/uso terapêutico , Animais , Sobrevivência Celular , Proteínas de Ligação a DNA/metabolismo , Camundongos Transgênicos , Microfluídica/instrumentação , Neurônios Motores/efeitos dos fármacos , Mutação/genética , Agregados Proteicos , Sirolimo/farmacologia , Transgenes
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