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.