Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia

Neurobiol Aging. 2019 Jan:73:229.e5-229.e9. doi: 10.1016/j.neurobiolaging.2018.08.015. Epub 2018 Aug 24.

Abstract

Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p = 0.0026).

Keywords: Familial amyotrophic lateral sclerosis (FALS); Frontotemporal dementia (FTD); Spastic paraplegia (SP); UBQLN2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Autophagy-Related Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Dentate Gyrus / metabolism
  • Disease Progression
  • Female
  • Frontal Lobe / metabolism
  • Frontotemporal Dementia / genetics*
  • Humans
  • Inclusion Bodies / metabolism
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Paraplegia / genetics*
  • Phenotype
  • Sex Factors
  • Temporal Lobe / metabolism
  • Ubiquitins / genetics*
  • Ubiquitins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • TARDBP protein, human
  • UBQLN2 protein, human
  • Ubiquitins