KIRREL3, associated with intellectual disability and autism, functions as a presynaptic organizer and interacts with proteins with roles in neurodevelopment. A. K. Srivastava1, Y. F. Liu1, Y. Luo1,3, A. Chaubey1, H.-G. Kim2, S. M. Sowell1 1) J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC; 2) Department of OB/GYN, Institute of Molecular Medicine and Genetics, Georgia Regents University, GA; 3) Present address: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.

   A large body of evidence indicates dysfunction of the synapse (synapse formation and plasticity) as a major contributing factor in autism spectrum disorder (ASD) and intellectual disability (ID). Defects of the KIRREL3 gene, located at 11q24.2, which encodes a synaptic cell-adhesion molecule of the immunoglobulin (Ig) superfamily, have recently been identified in ID, ASD and in the neurocognitive delay associated with Jacobsen syndrome. However, the molecular mechanisms of its physiological actions remain largely unknown. We have functionally characterized KIRREL3 and determined that in neuronal cells, KIRREL3 localizes on the cell membrane, in selected areas in the cytoplasm as well as in punctate structures along the entire length of neurite processes. We further confirmed its co-localization with markers for the Golgi apparatus and secretory vesicles. Using deletion constructs, we determined that the fourth Ig-like domain in the KIRREL3 extracellular domain (ECD) might be crucial for the secretory vesicle sublocalization of KIRREL3. Importantly, we found that the ECD of KIRREL3 can be cleaved after transient transfection in neuronal cells. Using a mixed culture system, we observed that both the full-length KIRREL3 and cleaved ECD can promote clustering of synaptic vesicles indicating their potential roles as presynaptic organizers. To further gain an understanding of the physiological role of KIRREL3 in neurodevelopment, we have shown that its intracellular domain interacts with the X-linked ID-associated synaptic scaffolding protein CASK and KIRREL3-ECD interacts with brain expressed proteins MAP1B and MYO16. In addition, we identified a genomic deletion encompassing MAP1B in one patient with ID, microcephaly and seizures. We also identified deletions encompassing MYO16 in two unrelated patients with ID, autism and microcephaly. MAP1B is involved in the development of the actin-based membrane skeleton. MYO16 has been shown to indirectly affect actin cytoskeleton through its interaction with WAVE1 complex. Together these findings suggest a potential contribution of KIRREL3 in the local assembly of the F-actin cytoskeleton at presynaptic sites that potentially initiates synapse formation. Our findings provide further insight into understanding the molecular mechanisms underlying the physiological action of KIRREL3 and its role in neurodevelopment.

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