The Dense Core Vesicle Protein CADPS in Severe Epilepsy, Intellectual Disability, and Progressive Spasticity
Abstract number :
2.365
Submission category :
12. Genetics / 12A. Human Studies
Year :
2018
Submission ID :
498818
Source :
www.aesnet.org
Presentation date :
12/2/2018 4:04:48 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Michael S. Hildebrand, University of Melbourne; Mark F. Bennett, The Walter and Eliza Hall Institute; Amy Schneider, University of Melbourne; Alix Macdonald, Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health; Melanie
Rationale: Syndromes featuring seizures, intellectual disability and spastic paraparesis have known familial contributions Over 48 loci and 25 genes have been identified for hereditary spastic paraplegias, of which at least ten are dominantly inherited, and proteins involved in intracellular trafficking, mitochondrial metabolism, and myelination are disrupted. Here we implicate a new gene pathway in this genetically heterogeneous disorder. Methods: We studied a three-generation Australian family with childhood-onset tonic-clonic seizures and myoclonic jerks, developmental delay and regression, and spastic paraparesis. Mildly affected subjects just had seizures without spastic paraparesis or intellectual impairment. We performed exome sequencing of two severely affected sisters. Results: We identified a novel missense mutation (c.3952A>G; p.I1318V) in the CADPS gene encoding the calcium-dependent activator protein for secretion. Segregation analysis was consistent with dominant inheritance through the paternal line. The CADPS gene is intolerant to variation and the novel mutation is located towards the C-terminal end of the protein in a region known to mediate association of dense core vesicles with target membranes at presynaptic neuronal terminals. Key to this association is tethering to target membranes via high affinity with components of the SNARE complex, such as SNAP25 that has previously been implicated in epileptic encephalopathies. Conclusions: Our data supports perturbation of synaptic transmission at presynaptic terminals in this complex familial syndrome. We are now pursuing additional CADPS mutations in unrelated cases, and performing functional studies on fibroblast cell lines from family members to elucidate pathogenic mechanisms. Funding: This study was supported by National Health and Medical Research Council Program Grant (1091593) to S.F.B, and I.E.S., a Project Grant (1129054) to S.F.B, a Project Grant (1079058) to M.S.H, and a R.D. Wright Career Development Fellowship (1063799) to M.S.H.