16O Lost in translation: pathogenic translation of GGC repeats in novel and toxic proteins in oculopharyngodistal myopathy (OPDM)

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Boivin, M., Schmitt, L., Grandgirard, E., Morlet, B., Negroni, L., Goetz-Reiner, P., Lefebvre, E., Maglott, A., Eberling, P., Oulad-Abdelghami, M., Deng, J., Charlet-Berguerand, N.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.413

Oculopharyngodistal myopathy (OPDM, OMIM #164310) and oculopharyngeal myopathy with leukoencephalopathy (OPML, OMIM #618637) are rare autosomal dominant diseases characterized by adult-onset weakness and atrophy of skeletal muscles of the face, the pharynx, the eyelid and the distal limbs. At the histopathological level, OPDM and OPML muscle fibers are characterized by the presence of cytoplasmic rimmed vacuoles and intranuclear inclusions, which are both ubiquitin- and p62-positive but of unknown origin. Recently, the genetic cause of OPML was identified as an expansion of GGC repeats, however located in a long non-coding RNA, LOC642361. Of interest, several genetic causes of OPDM were also identified very recently as identical expansions of 50 to 200 GGC repeats, however located within genetic regions annotated as “non-coding” in at least 5 different genes: LRP12, GIPC1, NOTCH2NLC, RILPL1 and ABCD3. As a result, OPDM is now sub-divided in 5 sub-groups, OPDM type 1 to 5, according to the genetic localization of its causal expanded GGC microsatellite mutation. Here, we found that the GGC repeat expansions located either in LOC642361 and that causes OPML, within GIPC1 or NOTCH2NLC 5’UTRs responsible respectively of OPDM2 and 3, or within RILPL1 antisense transcript, which cause OPDM4, are all embedded in small, previously unrecognized ORFs. Consequently, all these different GGC repeat expansions are translated in novel polyGlycine-containing proteins. Importantly, antibodies developed against these various proteins stain the rimmed vacuoles and intranuclear inclusions typical of OPDM, confirming translation of these GGC repeat expansions into novel proteins in patients. Moreover, we developed cell models for OPML, OPDM2, OPDM3 and OPDM4 and found that these polyGlycine proteins form cytoplasmic and intranuclear inclusions and are toxic for muscle cells. We are now in the process to develop mouse models of OPDM and OPML and first data will be presented. Finally, we found a pharmaceutical compound that solubilizes polyGlycine aggregates and rescues viability of muscle cell cultures, thus bringing hope to develop therapeutical options for these neuromuscular diseases. To conclude, these data suggest a common mechanism of toxicity to the multiple GGC repeat expansions in OPDM and OPML: their translation into novel and toxic polyGlycine-containing proteins.