Olfactory bulb anomalies in KBG syndrome mouse model and patients

Abstract ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size. We further show relatively normal formation of olfactory bulb outer neuronal layers with a reduced density of progenitors, neuroblasts, and neurons in the olfactory bulb core. Finally, we demonstrate incomplete migration of neuroblasts along the postnatal rostral migratory stream, which results in a decreased cell density in the olfactory bulb core. We also describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.