Project description:Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca2+) signaling and activity-dependent gene expression and show abnormalities in differentiation. Neurons from individuals with Timothy syndrome show increased expression of markers of the upper cortical layer and decreased expression of callosal projection markers. In addition, the mutation that causes Timothy syndrome leads to an increase in the production of neurons that synthesize norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase and atypical L-type–channel blocker. These findings provide strong evidence that Cav1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome. Total RNA was isolated from control and TS cells: fibroblasts, iPSCs, neurospheres (at day 7 in suspension), neurons at rest (day 45 of differentiation) and neurons kept in 67mM KCl for 9h. For sample titles, D1,D2 and D3 represent independent differentiation experiments. The number after - represents the iPSC cell line number. GSE25542_non-normalized.txt.gz contains data for 5 outliers.
Project description:Mutation of marA, rob, and soxS causes a clinical strain of E.coli to be attenuated at d3 post-infection in a mouse model of pyelonephritis, here we extract RNA at d2 post infection to analyze transcriptional differences between the two strains.
2010-10-01 | GSE23417 | GEO
Project description:Gene Mutation Causes a Syndrome of Combined Immunodeficiency
Project description:Mutation of one allele of the KAT6A gene encoding the histone acetyltransferase KAT6A (MOZ, MYST3) causes Arboleda-Tham-Syndrome (ARTHS), which is characterised by developmental delay, cognitive impairment and autism-like behaviours. We used mice to examine the effects of Kat6a mutations on gene expression in the develping cerebral cortex and cortical neurons. We examined the effects of homozygous and heterozygous loss of Kat6a on gene expression in the E12.5 dorsal telecencephalon, the embryonic precursor of the cerebral cortex, and the effects of heterozygous loss of Kat6a on gene expression in foetal cortical neurons.
Project description:Col8a2 mutation is one of the genetic causes of Fuchs endothelial corneal dystrophy (FECD). The Col8a2Q455K homozygous mutant mouse serves as a disease model for FECD. Corneal endothelial cells were isolated from early-stage (≤ 2 months old) and late-stage (≥ 8 months old) Col8a2Q455K homozygous mutant mice and their age-matched wild-type controls. This study investigates transcriptomic alterations associated with FECD progression caused by the Col8a2 mutation.
Project description:Hypotonia, ataxia, developmental delay and tooth enamel defect syndrome (HADDTS) is a recently identified syndrome linked to a heterozygous mutation in the C-Terminal Binding Protein 1 (CTBP1) transcriptional corepressor. The mutation is located within the major binding cleft (PXDLS), crucial for CtBP1’s interaction with proteins that regulate gene expression. We generated isogenic induced pluripotent cell lines (iPSCs) with the CTBP1 mutation in heterozygous and homozygous using CRISPR/Cas9 editing method. The transcriptional profile of iPSC-derived early neurons from isogenic wild-type and CTBP1 heterozygous and homozygous mutants was determined by RNA sequencing. The RNA-Seq data revealed downregulation of several key transcriptional factors, with homozygous mutations causing more pronounced downregulation than heterozygous mutations. Isogenic mutant neural stem cells (NSCs) exhibited less adhesion, migration, and calcium dysregulation, and mutant neurons showed premature neurite outgrowth. Our transcriptome and biological results provide novel insight into the mechanism of CTBP1 p.R342W mutation's role in the defective neurodevelopmental process.
Project description:Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca2+) signaling and activity-dependent gene expression and show abnormalities in differentiation. Neurons from individuals with Timothy syndrome show increased expression of markers of the upper cortical layer and decreased expression of callosal projection markers. In addition, the mutation that causes Timothy syndrome leads to an increase in the production of neurons that synthesize norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase and atypical L-type–channel blocker. These findings provide strong evidence that Cav1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.