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

Manon Boivin, Jianwen Deng, V. ronique Pfister, Erwan Grandgirard, Mustapha Oulad-Abdelghani, Bastien Morlet, Frank Ruffenach, Luc Negroni, Pascale Koebel, Hugues Jacob, Fabrice Riet, Anke A. Dijkstra, Kathryn McFadden, Wiley A. Clayton, Daojun Hong, Hiroaki Miyahara, Yasushi Iwasaki, Jun Sone, Zhaoxia Wang, Nicolas Charlet-Berguerand*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1825-1835.e5
JournalNeuron
Volume109
Issue number11
DOIs
Publication statusPublished - 2 Jun 2021

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