Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia

Newton T, Allison R, Edgar JR, Lumb JH, Rodger CE, Manna PT, Rizo T, Kohl Z, Nygren AOH, Arning L, Schuele R, Depienne C, Goldberg L, Frahm C, Stevanin G, Durr A, Schoels L, Winner B, Beetz C, Reid E (2018)


Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 141

Pages Range: 1286-1299

DOI: 10.1093/brain/awy034

Abstract

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

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APA:

Newton, T., Allison, R., Edgar, J.R., Lumb, J.H., Rodger, C.E., Manna, P.T.,... Reid, E. (2018). Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia. Brain, 141, 1286-1299. https://doi.org/10.1093/brain/awy034

MLA:

Newton, Timothy, et al. "Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia." Brain 141 (2018): 1286-1299.

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