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

Timothy Mark Newton ,Larissa Arning,Christian Beetz,Christiane Frahm,Rebecca Schüle,Giovanni Stevanin,Tania Rizo,Rachel Allison,Christel Depienne,Zacharias Kohl,Beate Winner,Evan Reid,Lüdger Schöls ,Alexandra Dürr ,Anders O.h Nygren ,Paul T Manna ,Catherine E Rodger ,Jennifer H Lumb ,James R Edgar ,Lisa V Goldberg

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.

Highlights

A hallmark of many genetic neurodegenerative disorders is variable expression within affected families, often exemplified by variations in disease age at onset
We found that cultured cells lacking DPY30 had increased endosomal tubulation, defective traffic of mannose 6-phosphate receptors (M6PRs) from endosomes to the Golgi apparatus, and abnormal lysosomal ultrastructural appearances that were highly similar to those seen in spastin-hereditary spastic paraplegias (HSPs) models
In this study we identify an epistatic interaction between SPAST and DPY30 that influences age at onset in spastinHSP

Summary

Introduction

A hallmark of many genetic neurodegenerative disorders is variable expression within affected families, often exemplified by variations in disease age at onset. Typically those caused by triplet repeat expansions, this variability is explained by the dynamic nature of the mutation (Orr and Zoghbi, 2007). In conditions where the pathogenic mutation is static, epistatic effects, where alleles at other genes modify the disease phenotype, are often suggested as an explanation. The underlying biological basis for such epistatic effects may involve additive deleterious effects on cellular pathways in which the proteins encoded by the disease and modifier gene both participate. In human single gene disease in general, and in neurodegenerative disease in particular, there are few examples where the underlying functional basis for such an epistatic effect has been explained. HSP is caused by mutations in many genes (Hensiek et al, 2015), mutations in SPAST ( known as SPG4) are by far the most frequent, affecting up to 60% of families with autosomal dominant HSP, and around 10–20% of cases unselected by family history (Hazan et al, 1999; Fonknechten et al, 2000; Sauter et al, 2002; Schule et al, 2016)

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