Olfactory bulb anomalies in KBG syndrome mouse model and patients

INTRODUCTION: ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder that is named after the first three families diagnosed. KBG syndrome patients display aberrant brain development, global developmental delay, autism, and intellectual disability. The brain is built by neural stem cells, which must generate neurons and glia (non-neuronal cells oligodendrocytes and astrocytes) in a strict spatio-temporal manner. The olfactory bulb (OB) is part of the brain that is responsible for olfaction (sense of smell). Reduction or loss of olfaction is linked to behavioural changes in patients with mental or neurodevelopmental disorders, like schizophrenia. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed KBG syndrome patients. METHODS: We used a mouse model where Ankrd11 is inducibly knocked out in neural stem cells using a Cre/Lox system. Ankrd11 knockout was induced with tamoxifen injection at embryonic day (E) 14, a time point prior to the complete formation of the OB. OB formation was then analyzed during embryonic, and postnatal development. OB phenotypes in KBG syndrome patients were recorded via magnetic resonance imaging (MRI) and/or clinical observations. RESULTS: Conditional knockout of Ankrd11 in murine embryonic neural stem cells resulted in aberrant postnatal olfactory bulb development and reduced size. We further showed 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 demonstrated incomplete migration of neuroblasts along the postnatal rostral migratory stream, which results in a decreased cell density in the olfactory bulb core. We also described two clinically and molecularly confirmed KBG syndrome patients with anosmia (lack of smell) and OB structure perturbations, such as and hypo-dysgenesis/agenesis (reduction or lack of OB structures). CONCLUSIONS: Our work contributes significantly to the OB development and neurodevelopmental disorders fields and has important translational implications. First, our report establishes a strong causative link between ANKRD11 perturbations and OB deficiencies in mice and humans. From a basic science and mechanistic perspective, our results indicate a critical role of Ankrd11 in neural stem cell migration. From a clinical perspective, our work suggests OB size or olfaction evaluations should be considered upon KBG syndrome diagnosis for appropriate genetic counselling and to improve clinical care.