Genetics, Gene Therapy & Genetic Disease
Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germlineA TPP1 mutation known to cause telomere shortening and bone marrow failure in humans recapitulates telomere loss but results in severe germline defects in mice without impacting murine hematopoiesis.
Activation of mitochondrial unfolded protein response protects against multiple exogenous stressorsThis work highlights the importance of the mitochondrial unfolded protein response in allowing organisms to survive external stressors through up-regulation of other stress response pathways.
INPP5K and Atlastin-1 maintain the nonuniform distribution of ER–plasma membrane contacts in neuronsCIL-1 and ATLN-1 maintain the balance between ER tubules and sheets and prevent invasion of cortical ER sheets into the axon, contributing to the non-uniform distribution of neuronal ER-PM contacts.
Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage responseThis work studies known and new ADPRHL2 mutations with different disease mechanisms overall indicating that loss of nuclear ARH3 alone is pathogenic via dysregulated nuclear ADP ribosylation.
High levels of TFAM repress mammalian mitochondrial DNA transcription in vivoThe TFAM-to-mtDNA ratio is critically important and must be maintained within a physiological range to allow normal mtDNA expression and prevent nucleoid hypercompaction in different mouse tissues.
Paralogous synthetic lethality underlies genetic dependencies of the cancer-mutated gene STAG2The context-dependency of genetic interactions of the cohesin gene STAG2, specifically STAG1 and the iron regulatory gene IREB2, are revealed by CRISPR-Cas9 screening in three different cellular backgrounds.
Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 miceThis work highlights the importance of CNS transduction for treatment of neurological diseases, a finding with significant clinical implications considering the long-lasting effects of gene therapy.
Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoidsHere, the authors evaluate prime editing in human adult stem cell–derived organoids. TP53 mutations are modeled in hepatocyte and colon organoids and the clinical application of prime editing is evaluated by repairing mutations in CFTR without genome-wide off-targets.
Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic KrasG12D in pancreatic cancerThis work identifies the use of exosomes to specifically deliver CRISPR/Cas9 to target oncogenic KrasG12D mutation in pancreatic cancer as a nonviral therapeutic strategy.
Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and DrosophilaCRISPR knockout of msl-2 and epigenome analyses in Anopheles reveal that X chromosome dosage compensation in mosquitos and Drosophila is achieved by two different molecular mechanisms.