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

J Exp Med. 2020 Oct 5;217(10):e20192040. doi: 10.1084/jem.20192040.

Nicole J Van Bergen ¹ ², Syed Mukhtar Ahmed ³, Felicity Collins ⁴ ⁵, Mark Cowley ⁶ ⁷ ⁸, Annalisa Vetro ⁹, Russell C Dale ¹⁰ ¹¹, Daniella H Hock ¹², Christian de Caestecker ³, Minal Menezes ¹³, Sean Massey ¹, Gladys Ho ⁴, Tiziana Pisano ⁹, Seana Glover ¹ ², Jovanka Gusman ¹ ², David A Stroud ¹², Marcel Dinger ⁶ ¹⁴, Renzo Guerrini ⁹, Ian G Macara ³, John Christodoulou ¹ ² ¹⁵

Affiliations

1 Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
2 Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN.
4 Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
5 Medical Genomics Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
6 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
7 St Vincent's Clinical School, University of New South Wales Sydney, Sydney, New South Wales, Australia.
8 Children's Cancer Institute, Kensington, New South Wales, Australia.
9 Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy.
10 Department of Paediatric Neurology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
11 Kids Neuroscience Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
12 Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
13 Kids Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
14 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington Campus, Sydney, New South Wales, Australia.
15 Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Victoria, Australia.

PMID: 32639540 DOI: 10.1084/jem.20192040

Abstract

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.

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