UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration

Ann Neurol. 2014 May;75(5):793-798. doi: 10.1002/ana.24164. Epub 2014 May 9.


We report a 5-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2-positive inclusions were identified in brain, we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Adult
  • Aged
  • Autophagy-Related Proteins
  • Cell Cycle Proteins / genetics*
  • Child, Preschool
  • Female
  • Genes, Dominant
  • Genetic Heterogeneity*
  • Heredodegenerative Disorders, Nervous System / diagnosis*
  • Heredodegenerative Disorders, Nervous System / genetics*
  • Humans
  • Male
  • Mutation / genetics*
  • Pedigree
  • Protein Folding
  • Ubiquitins / genetics*
  • Young Adult


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