Abstract
Microsatellite expansions cause more than 40 neurological disorders, including Huntington's disease, myotonic dystrophy, and C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). These repeat expansion mutations can produce repeat-associated non-ATG (RAN) proteins in all three reading frames, which accumulate in disease-relevant tissues. There has been considerable interest in RAN protein products and their downstream consequences, particularly for the dipeptide proteins found in C9ORF72 ALS/FTD. Understanding how RAN translation occurs, what cellular factors contribute to RAN protein accumulation, and how these proteins contribute to disease should lead to a better understanding of the basic mechanisms of gene expression and human disease.
Highlights
Introduction and backgroundMore than 40 different neurological diseases are caused by unstable microsatellite sequences (e.g. CAG, CCG, or G4C2) that are repeated multiple times at specific human genetic loci
repeat-associated non-ATG (RAN) proteins have been reported in eight repeat expansion disorders with different repeat motifs, pathogenic thresholds, and disease presentations
Significant progress has been made in understanding the role of RAN proteins in disease, additional insights into the mechanisms of RAN translation will facilitate the identification of new therapeutic targets and advance our understanding of cell biology and protein
Summary
Microsatellite expansions cause more than 40 neurological disorders, including Huntington’s disease, myotonic dystrophy, and C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). These repeat expansion mutations can produce repeat-associated non-ATG (RAN) proteins in all three reading frames, which accumulate in disease-relevant tissues. There has been considerable interest in RAN protein products and their downstream consequences, for the dipeptide proteins found in C9ORF72 ALS/FTD. Understanding how RAN translation occurs, what cellular factors contribute to RAN protein accumulation, and how these proteins contribute to disease should lead to a better understanding of the basic mechanisms of gene expression and human disease
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