GGC repeat expansions within new open reading frames are translated into toxic polyglycine proteins in oculopharyngodistal myopathy
A total of 3-6% human genome is composed of microsatellite sequences, which are short DNA elements composed of two to six nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as noncoding, which raises questions about their pathogenicity. Here we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without oculopharyngeal myopathy leukoencephalopathy are located within previously unrecognized open reading frames (ORFs), resulting in their translation into new polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting the expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet-unrecognized small ORFs.
Authors
- Damien Plassard (ORCID: https://orcid.org/0000-0001-8569-6163)
- Nobuyuki Eura (ORCID: https://orcid.org/0000-0002-4943-3152)
- Jiaxi Yu (ORCID: https://orcid.org/0000-0002-6458-5226)
- Bastien Morlet (ORCID: https://orcid.org/0000-0001-6058-7366)
- Pascal Eberling
- Paola Rossolillo
- Angélique Pichot
- Erwan Grandgirard (ORCID: https://orcid.org/0000-0002-5263-2144)
- Manon Boivin (ORCID: https://orcid.org/0000-0003-4055-9733)
- N Wang
- Muriel Philipps (ORCID: https://orcid.org/0000-0003-0108-6689)
- Elise Lefebvre
- David Pietri
- Anne Maglott
- Christelle Thibault
- Chadia Nahy
- Nicolas Charlet-Berguerand
- Jianwen Deng
- Zhaoxia Wang
- Mustapha Oulad-Abdelghani
- Chao Gao
- Patrice Goetz-Reiner
- Léa Schmitt
- Kang Yang
Institutions
- Centre National de la Recherche Scientifique (FR)
- Fujian Medical University (CN)
- Inserm (FR)
- Peking University (CN)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- National Center of Neurology and Psychiatry (JP)
- First Affiliated Hospital of Fujian Medical University (CN)
- Peking University First Hospital (CN)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-02-17
- DOI
- https://doi.org/10.1038/s41588-026-02507-z
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Peking University First Hospital
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- National Natural Science Foundation of China
- Fondation pour la Recherche Médicale
- Université de Strasbourg
- Centre National de la Recherche Scientifique
- Peking University
- Beijing Nova Program