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

Brain : a Journal of Neurology
Timothy NewtonEvan Reid

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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Citations

Dec 7, 2018·Human Molecular Genetics·Liang QiangPeter W Baas
Dec 19, 2019·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova·G E RudenskayaO P Ryzhkova
Oct 21, 2019·Molecular Diagnosis & Therapy·Miao ZhaoXiang Lin
Aug 30, 2020·Annals of Clinical and Translational Neurology·Lu-Lu LaiXiang Lin
Dec 12, 2018·Frontiers in Neurology·Dana M Bis-Brewer, Stephan Züchner
Mar 16, 2019·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova·G E RudenskayaO P Ryzhkova
Dec 4, 2019·Frontiers in Neuroscience·Rachel AllisonEvan Reid
Feb 19, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Mehrdad A EstiarZiv Gan-Or
Apr 18, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Hao Jiang
Aug 28, 2021·Brain Sciences·Neha MohanPeter W Baas
Dec 14, 2021·Frontiers in Molecular Biosciences·Liena E O ElsayedGiovanni Stevanin

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