The polyG diseases: a new disease entity

Abstract

Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5' untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

Keywords: Fragile X-associated tremor/ataxia syndrome; Neuronal intranuclear inclusion disease; Oculopharyngeal myopathy with leukoencephalopathy; Oculopharyngodistal myopathy; PolyG diseases.

Fig. 1

Typical brain radiological and pathological features in patient with NOTCH2NLC-CGG expansion. A and B Representative brain DWI image and T2-weighted image of patients with NOTCH2NLC-related polyG disease. C Representative H&E staining image show eosinophilic NIIs (black arrow) in sweat gland cells of skin D Representative immunostaining image show p62-positive NIIs (black arrow) in skin. E Representative electron microscopy image revealed Intranuclear tubulofilamentous inclusions in the skin of NIID patient. F Immunofluorescence against uN2CpolyG using 4D12 antibody (red, generously providing by Dr. Nicolas Charlet-Berguerand) and p62 antibody (green) on brain section from patient with NOTCH2NLC-CGG repeat expansion. Nuclei were counterstained with DAPI

Fig. 2

Main mechanisms associated with polyG diseases. A CGG repeats are triplet nucleotides located in non-coding regions. There are two main pathogenesis mechanisms of non-coding CGG expansion related diseases. Mild and moderate CGG repeats can translate into polyglycine, and the protein toxicity causes neurodegeneration disorders, including FXTAS and NIID. In contrast, a high degree of repeated CGG sequences will lead to CpG island hypermethylation. Hypermethylation of CpG can lead to transcriptional gene silencing, resulting in partial or complete loss of the native protein encoded by the gene, resulting in abnormal FXS or asymptomatic NIID. B Hypotheses for the mechanism of nuclear inclusion body formation. CGG repeat RNAs can fold into complex structures, including hairpins, which aberrantly interact with and sequester RBPs into RNA foci. Non-coding RNA repeats could undergo canonical ribosome-dependent translation mechanism, thereby producing toxic polyG peptides. C Possible therapeutic approaches for polyG diseases. ASOs can bind to mRNA that contains pathological repeat expansions, inducing degradation of the target RNA. Small molecules can interact with mutant mRNA and break the hairpin structure. CRISPR/Cas9 technology can be used to excise portions of CGG repeats to inhibit methylation or translation of toxic proteins