Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.
Brain. 2018-02-22; 141(5): 1286-1299
DOI: 10.1093/brain/awy034
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1. Brain. 2018 May 1;141(5):1286-1299. doi: 10.1093/brain/awy034.
Mechanistic basis of an epistatic interaction reducing age at onset in hereditary
spastic paraplegia.
Newton T(1), Allison R(1), Edgar JR(2), Lumb JH(1), Rodger CE(1), Manna PT(2),
Rizo T(3), Kohl Z(4), Nygren AOH(5), Arning L(6), Schüle R(7)(8), Depienne
C(9)(10), Goldberg L(11), Frahm C(12), Stevanin G(9)(10)(13), Durr A(9)(10),
Schöls L(7)(8), Winner B(4), Beetz C(11), Reid E(1).
Author information:
(1)Department of Medical Genetics and Cambridge Institute for Medical Research,
University of Cambridge, UK.
(2)Department of Clinical Biochemistry and Cambridge Institute for Medical
Research, University of Cambridge, Cambridge CB2 0XY, UK.
(3)Department of Stem Cell Biology, Friedrich-Alexander University
Erlangen-Nuernberg (FAU), Erlangen, Germany.
(4)Department of Molecular Neurology, Friedrich-Alexander University
Erlangen-Nuernberg (FAU), Erlangen, Germany.
(5)MRC-Holland, Amsterdam, The Netherlands.
(6)Department of Human Genetics, Ruhr-University, Bochum, Germany.
(7)Center for Neurology and Hertie Institute for Clinical Brain Research,
Eberhard-Karls-University, 72076 Tübingen, Germany.
(8)German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
(9)ICM Brain and Spine Institute, INSERM U1127, CNRS UMR7225, Sorbonne
Universites, UPMC Univ Paris VI UMR_S1127, Paris, France.
(10)APHP, Genetic Department, Pitie-Salpêtrière University Hospital, Paris,
France.
(11)Department of Clinical Chemistry and Laboratory Diagnostics, Jena University
Hospital, Jena, Germany.
(12)Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
(13)Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France.
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.
DOI: 10.1093/brain/awy034
PMCID: PMC5917785
PMID: 29481671 [Indexed for MEDLINE]