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.

Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy

“…These changes were present bilaterally and together imply increased cortical responsiveness to direct stimulation. This increased responsiveness is consistent with the augmented seizure susceptibility observed in Mbnl2 KO mice (Charizanis et al 2012) and in the DMSXL transgenic model of DM that expresses a human DMPK transgene with CTG expansion ranging from 1200–1700 in length (Gomes-Pereira et al 2007). There have been a small number of case reports showing comorbidity of epilepsy in DM1 (Worku 2014;Kajal et al 2017) and DM2 (Cagnetti et al 2014;Giuliano et al 2016), however there has been no definitive link between increased seizure susceptibility and DM.…”

“…Mouse models that demonstrate missplicing and/ or loss of MBNL proteins reproduce many of the systemic and CNS splicing abnormalities (Gomes-Pereira et al 2007;Du et al 2010;Charizanis et al 2012;Suenaga et al 2012;Hernandez-Hernandez et al 2013). The sequestration of splicing factors by repeat expansion RNA transcripts not only provides for a compelling model of disease pathogenesis but also a potential therapeutic approach to DM based on upregulation of members of the MBNL family (Chamberlain and Ranum 2012).…”

Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1

“…DMSXL mice show the highest level of expression of CTG repeats and nuclear DMPK mRNA foci in cardiac and skeletal muscles [16,17]. Housing and handling of mice were performed in accordance with the guidelines established by the French Council on Animal Care "Guide for the Care and Use of Laboratory Animals": EEC86/609 Council Directive -Decree 2001-131.…”

Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders

“…DM1 polyGln-RAN proteins were found at low frequency in patient myoblasts, skeletal muscle and heart and were more common in blood. The co-localization of DM1-polyGln aggregates with caspase-8 [12], an early indicator of polyGln-induced apoptosis [22], is consistent with a role for polyGln toxicity in DM1 [23] (Table 1). …”