Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

Neuron. 2021 Jun 2;109(11):1825-1835.e5. doi: 10.1016/j.neuron.2021.03.038. Epub 2021 Apr 21.


Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.

Keywords: RAN translation; genetic diseases; neurodegeneration; polyG; polyglycine; trinucleotide repeat disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Intranuclear Inclusion Bodies / genetics
  • Intranuclear Inclusion Bodies / metabolism
  • Intranuclear Inclusion Bodies / pathology
  • Locomotion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Open Reading Frames
  • Peptides / genetics
  • Peptides / metabolism
  • Peptides / toxicity*
  • Trinucleotide Repeat Expansion*


  • Peptides
  • polyglycine

Supplementary concepts

  • Neuronal intranuclear inclusion disease