Akademik Veri Yönetim Sistemi
47th FEBS Congress, Tours, Fransa, 8 - 12 Temmuz 2023, cilt.13, ss.246
During a whole exome sequence (WES) screen aiming to identify novel candidate geneticmutations that cause neurodevelopmental disorders in pediatric patients, we detected an 11bp deletion mutation in the ATG9B gene. The patients, children of a consanguineousmarriage, displayed mental retardation, facial dysmorphia, obesity, and behavioralabnormalities. The deletion mutation resulted in frameshift and addition of a prematureSTOP codon, truncating the ATG9B protein. This is a novel autosomal recessive geneticdisorder, also the first genetic disease linked with ATG9B. ATG9B is a homolog of ATG9A, aubiquitously expressed autophagy mediator that acts as intracellular membrane carriertowards phagophore assembly sites. There is plenty of literature on ATG9A and its roles inautophagy. However, ATG9B, whose expression is restricted to placenta and pituitary gland,has not been investigated. We hypothesized; the clinical anomalies observed in patientsresulted from abnormal placental development due to ATG9B truncation. When expressedin mammalian cells, the mutant ATG9B aggregates and sequesters in a perinuclearcompartment while WT protein displays a distribution similar to ATG9A and localizes asperinuclear and cytosolic puncta. We generated ATG9B knockin mice by inserting a STOPcodon at the mutation site, and constitutive ATG9B KO mice by exon deletion. Homozygousknockin and knockout mice were viable. Currently, we are phenotyping the mouse modelsby analyzing the development, autophagy and apoptosis in placental histological sections.Behavioral tests are in progress. In summary, we identified a novel rare genetic disease,generated transgenic knockin and knockout mouse models, and we expect to accumulateadditional data on the disease etiology and ATG9B’s functions during placental developmentby FEBS 2023. This project is completely novel, aims to present a novel genetic disease within depth characterization, ready to start strategizing potential remedies