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

Brain. 2018 May 1;141(5):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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • CD8 Antigens / genetics
  • CD8 Antigens / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epistasis, Genetic / genetics*
  • Female
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • HeLa Cells / metabolism
  • HeLa Cells / ultrastructure
  • Humans
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Lysosomal-Associated Membrane Protein 1 / ultrastructure
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Middle Aged
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / ultrastructure
  • Protein Transport / genetics
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastin / genetics*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ARFGEF1 protein, human
  • ASH2L protein, human
  • CD8 Antigens
  • DNA-Binding Proteins
  • DPY30 protein, human
  • GOLPH3 protein, human
  • Guanine Nucleotide Exchange Factors
  • Lysosomal-Associated Membrane Protein 1
  • Membrane Proteins
  • Nuclear Proteins
  • RBBP5 protein, human
  • Transcription Factors
  • Spastin
  • SPAST protein, human