Proteomic sequencing of ADAM17 deficiency mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Ming Li
PROVIDER: PXD049459 | iProX | Fri Feb 16 00:00:00 GMT 2024
REPOSITORIES: iProX
Similar Datasets
Project description:The microRNA miR-96 is important for hearing; mutations in the seed region result in dominant progressive hearing loss in mice and humans. Mir96 is expressed in the sensory hair cells of the organ of Corti along with Mir182 and Mir183. miR-96 is a master regulator of hair cell development, controlling many genes in the organ of Corti, but the role of miR-182 and miR-183 in the hair cells is unknown. We carried out RNA-seq on mice carrying a knockout allele of Mir182, and mice carrying a double knockout allele of Mir183 and Mir96 (Mir183/96). RNA was extracted from the organ of Corti from P4 homozygotes and sex-matched wildtype littermates. Strand-specific libraries were prepared using the NuGEN Ovation Mouse RNA-Seq System 1-16 kit and sequenced on an Illumina HiSeq 2500 machine as paired-end 125bp reads.
2019-03-15 | E-MTAB-5800 | biostudies-arrayexpress
Project description:Recessive single-nucleotide mutations in MARS2 are causative for a mitochondrial translation deficiency disorder with a primary phenotype including developmental delay, sensorineural hearing loss, and hypotonia. We generated a mouse model of MARS2 deficiency by introduction of the p.R135W mutation, the sequence homolog of the human p.R142W mutation.
2023-12-21 | GSE172286 | GEO
Project description:The homeostasis of both cornea and hair follicles depends on a constant supply of progeny cells produced by populations of keratin (K) 14-expressing stem cells localized in specific niches. To investigate the potential role of Co-factors of LIM domains (Clims) in such tissues, we generated transgenic mice expressing a dominant-negative Clim molecule (DN-Clim) under the control of the K14 promoter. As expected, the K14 promoter directed high level expression of the transgene to the basal cells of cornea and epidermis, as well as the outer root sheath of hair follicles. In corneal epithelium, the transgene expression causes decreased expression of adhesion molecule BP180 and defective hemidesmosomes, leading to detachment of corneal epithelium from the underlying stroma, which in turn causes blisters, wounds and an inflammatory response. After a period of epithelial thinning, the corneal epithelium undergoes differentiation to an epidermis-like structure. The K14-DN-Clim mice also develop progressive hair loss due to dysfunctional hair follicles that fail to generate hair shafts. The number of hair follicle stem cells is decreased by at least 50% in K14-DN-Clim mice, indicating that Clims are required for hair follicle stem cell maintenance. We hypothesize that Clim2 is an essential co-factor for the LIM homeodomain factor Lhx2, which was previously shown to play a role in hair follicle stem cell maintenance. Together, these data indicate that Clim proteins play important roles in the homeostasis of corneal epithelium and hair follicles. Experiment Overall Design: We profiled mRNA expression in mouse back skin from 3 time points, representing the initial hair follicle morphogenesis (P6 and P14) and the first telogen (P23); hair growth is synchronized during these time points. For each time point, RNA was isolated and analyzed from 3 to 5 transgenic mice and same number of wild-type littermates.
2008-06-16 | E-GEOD-8227 | biostudies-arrayexpress
Project description:The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a novel, heterozygous variant in TLK1 (c.1435C>G, p.Q479E) by genome sequencing (GS). Transcriptome sequencing in patient-derived cells confirmed expression of TLK1 transcripts carrying the p.Q479E variant and revealed alterations in genes involved in class switch recombination and cytokine signaling.
2023-08-18 | GSE241032 | GEO
Project description:Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis¬. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations in the HARS catalytic domain are associated with Charcot Marie Tooth Disease Type 2W (CMT2W), while anticodon-binding domain mutations cause Usher Syndrome Type IIIB (USH3B). We use yeast as a model system to study disease-causing HARS mutations (V133F, V155G, Y330C, S356N) associated with CMT2W, and Y454S, associated with USH3B. All human HARS variants complemented genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, result in reduced growth. HARS V155G and S356N cause accumulation of insoluble proteins and mistranslation in yeast, and the growth defect of these mutants was rescued by histidine addition to the growth media, restoring the soluble proteome. V133F and Y330C, on the other hand, lead to decreased HARS abundance. Histidine supplementation further reduced viability in yeast expressing V133F and Y330C, and lead to insoluble protein accumulation, indicating histidine toxicity associated with these mutants. Because histidine is in clinical trials as treatment for USH3B, our data will inform future treatment options for these as well as CMT patients, where histidine supplementation may either have a toxic or compensating effect dependingon the nature of the causative HARS variant.
2023-03-10 | PXD034865 | Pride
Project description:Autism spectrum disorder (ASD) includes a series of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneous disease phenotypes, possibly due to functional diversity of generated isoforms. Increasing evidence indicates such phenomenon in SHANK2, a causative gene in ASD; however, there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here we reported a patient-derived mutation on SHANK2, hitting only the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X.
2024-05-01 | GSE256210 | GEO
Project description:The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a heterozygous TLK1 variant (c.1435C>G, p.Q479E), as well as a mutation in MDM1 (c.1197dupT, p.K400*). Cells expressing TLK1 p.Q479E exhibited reduced cytokine responses and elevated DNA damage, but not increased radiation sensitivity or DNA repair defects. The TLK1 p.Q479E variant impaired kinase activity but not proximal protein interactions.
2024-04-30 | GSE266289 | GEO
Project description:Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss of function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the Cysteine 19 residue to phenylalanine or tyrosine. These individuals presented with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulated most of the skeletal anomalies observed in the affected individuals. We demonstrated that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Our findings support that heterozygous variants in MGP altering Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.
2024-01-26 | PXD043374 | Pride
Project description:Proteins of the human hair shaft contain a wealth of information about the coding regions of the person’s genome from whom the hair is derived. Commonly found at crime scenes, hair shafts may thus provide useful forensic evidence if the information they contain can be exploited. Present experiments show that hair shafts from four different anatomic sites are similarly useful in distinguishing individuals by protein profiling. However, the results demonstrated that protein profiles were dependent on anatomic site, indicating that a proper comparison requires matching the sites of origin. The differences in profile offer the prospect of determining the site of origin of hair by comparison with profiles of shafts from other anatomic sites. By contrast, the genetically variant peptides detected in the protein digests, that map to non-synonymous single nucleotide polymorphisms in subject DNA, were detectable regardless of the anatomic origin of the hair shafts. The resulting profiles of genetically variant peptides were more dependent on a subject’s genotype than on the anatomic origin of the hair shaft. Individual identification therefore can be based on peptide profiles regardless of body location. This study demonstrates the utility of proteomic analysis for increasing the forensic value of hair shaft evidence.
2019-04-04 | PXD011732 | Pride
Project description:A1AT deficiency is an autosomal not recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant retain polymerised protein in the endoplasmic reticulum of hepatocytes, predisposing them to liver disease. This study primarily aimed to uncover the molecular mechanisms that link protein misfolding to liver injury. To that end, RNA was extracted from hepatocytes differentiated from hIPSCs carrying the Z variant and mutation-corrected hIPSCs (control). The second objective of the study was to benchmark the gene expression profile of both hIPSC-derived hepatocytes types to primary hepatocytes of wild type and a Z variant A1AT genotype.
2018-06-26 | E-MTAB-6781 | biostudies-arrayexpress