CTG Trinucleotide Repeat “Big Jumps”: Large Expansions, Small Mice

Abstract

Trinucleotide repeat expansions are the genetic cause of numerous human diseases, including fragile X mental retardation, Huntington disease, and myotonic dystrophy type 1. Disease severity and age of onset are critically linked to expansion size. Previous mouse models of repeat instability have not recreated large intergenerational expansions (“big jumps”), observed when the repeat is transmitted from one generation to the next, and have never attained the very large tract lengths possible in humans. Here, we describe dramatic intergenerational CTG•CAG repeat expansions of several hundred repeats in a transgenic mouse model of myotonic dystrophy type 1, resulting in increasingly severe phenotypic and molecular abnormalities. Homozygous mice carrying over 700 trinucleotide repeats on both alleles display severely reduced body size and splicing abnormalities, notably in the central nervous system. Our findings demonstrate that large intergenerational trinucleotide repeat expansions can be recreated in mice, and endorse the use of transgenic mouse models to refine our understanding of triplet repeat expansion and the resulting pathogenesis. Many neurological and/or neuromuscular diseases, such as myotonic dystrophy, Huntington disease, and fragile X mental retardation are caused by an increase in the size of a repeated DNA sequence within a specific gene. These repetitive DNA sequences are prone to expansion, increasing in size when transmitted from one generation to the next, which results in more severe symptoms and earlier age of onset. In myotonic dystrophy, the DNA repeat can undergo very large increments of several hundred units (frequently called “big jumps”), usually associated with the most severe clinical picture. Until now, big jumps have not been observed in mice carrying the disease mutation, leading to questions about the adequacy of mice to fully model DNA repeat instability. We now report that these large increments in the size of DNA repeats can occur in transgenic mice, resulting in animals that carry extremely large repeated sequences. These mice are remarkably small and display abnormalities in the metabolism of multiple messenger RNAs, notably in brain and muscle. Our findings strongly support the use of transgenic mice to resolve the complex dynamics of simple repetitive DNA sequences associated with human inherited diseases, and to investigate the molecular events that underlie the development of disease symptoms.