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Mutations in the exocyst component EXOC2 cause severe defects in human brain development


Van Bergen NJ , Ahmed SM , Collins F , Cowley M , Vetro A , Dale RC , Hock DH , de Caestecker C , Menezes M , Massey S , Ho G , Pisano T , Glover S , Gusman J , Stroud DA , Dinger M , Guerrini R , Macara IG , Christodoulou J , . The Journal of experimental medicine. 2020 7 27; 217(10).


The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering and fusion of vesicles at the plasma membrane. We report pathogenic variants in an exocyst subunit, EXOC2 (Sec5). Affected individuals have severe developmental delay, dysmorphism, and brain abnormalities; variability associated with epilepsy; and poor motor skills. Family 1 had two offspring with a homozygous truncating variant in EXOC2 that leads to nonsense-mediated decay of EXOC2 transcript, a severe reduction in exocytosis and vesicle fusion, and undetectable levels of EXOC2 protein. The patient from Family 2 had a milder clinical phenotype and reduced exocytosis. Cells from both patients showed defective Arl13b localization to the primary cilium. The discovery of mutations that partially disable exocyst function provides valuable insight into this essential protein complex in neural development. Since EXOC2 and other exocyst complex subunits are critical to neuronal function, our findings suggest that EXOC2 variants are the cause of the patients’ neurological disorders.