Journal article

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

Nicole J Van Bergen, Syed Mukhtar Ahmed, Felicity Collins, Mark Cowley, Annalisa Vetro, Russell C Dale, Daniella H Hock, Christian de Caestecker, Minal Menezes, Sean Massey, Gladys Ho, Tiziana Pisano, Seana Glover, Jovanka Gusman, David A Stroud, Marcel Dinger, Renzo Guerrini, Ian G Macara, John Christodoulou



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 exocytos..

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Awarded by National Institutes of Health grant, Department of Health and Human Services

Awarded by National Health and Medical Research Council (NHMRC)

Awarded by Seventh Framework Programme, DESIRE project

Funding Acknowledgements

The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. Sequencing, data analysis, and Sanger validation were done at the Garvin Institute, Sydney, Australia. Funding to I.G. Macara was provided by National Institutes of Health grant GM070902, Department of Health and Human Services. We acknowledge funding from the National Health and Medical Research Council (NHMRC Project Grants 1140906 to D.A. Stroud and 116447 to J. Christodoulou and D.A. Stroud; NHMRC Fellowship 1140851 to D.A. Stroud). D.H. Hock is supported by a Melbourne International Research Scholarship. Research at Meyer Children's Hospital, University of Florence was funded by the Seventh Framework Programme, grant agreement no. 602531, DESIRE project. D.H. Hock was supported by the Mito Foundation PhD Top-up scholarship.