Abstract
Microsatellites are repeated DNA sequences of 3–6 nucleotides highly variable in length and sequence and that have important roles in genomes regulation and evolution. However, expansion of a subset of these microsatellites over a threshold size is responsible of more than 50 human genetic diseases. Interestingly, some of these disorders are caused by expansions of similar sequences, sizes and localizations and present striking similarities in clinical manifestations and histopathological features, which suggest a common mechanism of disease. Notably, five identical CGG repeat expansions, but located in different genes, are the causes of fragile X-associated tremor/ataxia syndrome (FXTAS), neuronal intranuclear inclusion disease (NIID), oculopharyngodistal myopathy type 1 to 3 (OPDM1-3) and oculopharyngeal myopathy with leukoencephalopathy (OPML), which are neuromuscular and neurodegenerative syndromes with overlapping symptoms and similar histopathological features, notably the presence of characteristic eosinophilic ubiquitin-positive intranuclear inclusions. In this review we summarize recent finding in neuronal intranuclear inclusion disease and FXTAS, where the causing CGG expansions were found to be embedded within small upstream ORFs (uORFs), resulting in their translation into novel proteins containing a stretch of polyglycine (polyG). Importantly, expression of these polyG proteins is toxic in animal models and is sufficient to reproduce the formation of ubiquitin-positive intranuclear inclusions. These data suggest the existence of a novel class of human genetic pathology, the polyG diseases, and question whether a similar mechanism may exist in other diseases, notably in OPDM and OPML.
Highlights
DNA short tandem repeats (STR), known as microsatellites, are short sequences of 3–6 nucleotides repeated multiple time so that they occupy as much as 2–3% of the human genome
In contrast to familial anticipation and correlation between expansion lengths and disease severity and/or age of onset observed in various microsatellite diseases (FXS, polyQ disorders, and myotonic dystrophy type 1, etc.), there are only few examples of anticipation reported in neuronal intranuclear inclusion disease (NIID) and oculopharyngodistal myopathy type to 3 (OPDM) families, and a limited correlation between the size of CGG expansions and the age of onset in oculopharyngodistal myopathy type 1 (OPDM1) and OPDM2, with a r2 of 0.188 and 0.158, respectively, (Kumutpongpanich et al, 2021; Xi et al, 2021)
Translation of CGG repeat expansions into simar polyglycinecontaining proteins in two neurodegenerative diseases with overlapping clinical manifestations and nearly identical histopathological features, fragile X-associated tremor/ataxia syndrome (FXTAS) and NIID, suggest the existence of a novel class of human genetic disorders, the polyG diseases. This model is inspired by the translation into toxic polyalanine- or polyglutamine-containing proteins of GCN or CAG repeat expansions embedded in the ORFs of diverse genes, resulting in the polyAla or polyQ diseases, respectively
Summary
In this review we summarize recent finding in neuronal intranuclear inclusion disease and FXTAS, where the causing CGG expansions were found to be embedded within small upstream ORFs (uORFs), resulting in their translation into novel proteins containing a stretch of polyglycine (polyG). Expression of these polyG proteins is toxic in animal models and is sufficient to reproduce the formation of ubiquitin-positive intranuclear inclusions.
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