Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability

Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset. F...

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Bibliographic Details
Published in:Human molecular genetics 2000-05, Vol.9 (8), p.1185-1194
Main Authors: SEZNEC, H, LIA-BALDINI, A.-S, DUROS, C, FOUQUET, C, LACROIX, C, HOFMANN-RADVANYI, H, JUNIEN, C, GOURDON, G
Format: Article
Language:English
Subjects:
3' Untranslated Regions - genetics
Animals
Biological and medical sciences
Cloning, Molecular
Diseases of striated muscles. Neuromuscular diseases
Female
Gene Library
Genomic Imprinting
Humans
Life Sciences
Male
Medical sciences
Mice
Mice, Transgenic
myotonic dystrophy
Myotonic Dystrophy - genetics
Myotonin-Protein Kinase
Neurology
Protein-Serine-Threonine Kinases - genetics
Recombinant Proteins - biosynthesis
Spermatozoa - physiology
Trinucleotide Repeats
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Summary:Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset. Furthermore, tissues from DM patients exhibit somatic mosaicism that increases with age. We generated transgenic mice carrying large human genomic sequences with 20, 55 or >300 CTG, cloned from patients from the same affected DM family. Using large human flanking sequences and a large amplification, we demonstrate that the intergenerational CTG repeat instability is reproduced in mice, with a strong bias towards expansions and with the same sex- and size-dependent characteristics as in humans. Moreover, a high level of instability, increasing with age, can be observed in tissues and in sperm. Although we did not observe dramatic expansions (or 'big jumps' over several hundred CTG repeats) as in congenital forms of DM, our model carrying >300 CTG is the first to show instability so close to the human DM situation. Our three models carrying different sizes of CTG repeat provide insight on the different factors modulating the CTG repeat instability.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/9.8.1185