Human Molecular Genetics, Vol 8, 2473-2478, Copyright © 1999 by Oxford University Press
DG Monckton, ML Cayuela, FK Gould, GJ Brock, R Silva and T Ashizawa
Genetic anticipation, i.e. increasing disease severity and decreasing age
of onset from one generation to the next, is observed in a number of
diseases, including myotonic dystrophy type 1, Huntington's disease and
several of the spinocerebellar ataxias. All of these disorders are
associated with the expansion of a trinucleotide repeat and array length is
positively correlated with disease severity and inversely correlated with
the age of onset. The expanded repeat is highly unstable and continues to
expand from one generation to the next, providing a molecular explanation
for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest
additions to the list of triplet repeat diseases and is distinct from the
other SCAs in that it is accompanied by retinal degeneration. Pedigree
analyses have previously revealed that the SCA7 repeat is highly unstable
and liable to expand, in particular when transmitted by a male.
Surprisingly, though, an under-representation of male transmission has also
been reported. We now demonstrate directly by single molecule analyses that
the expanded repeat is extraordinarily unstable in the male germline and
biased toward massive increases. Nearly all of the mutant sperm of two SCA7
males contain alleles that are so large that most of the affected offspring
would at best have a severe infantile form of the disease. Indeed, the
gross under-representation of such very large expanded alleles in patients
suggests that a significant proportion of such alleles might be associated
with embryonic lethality or dysfunctional sperm.
ARTICLES
Very large (CAG)(n) DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males
Division of Molecular Genetics, Institute for Biomedical and Life Sciences, University of Glasgow, Anderson College, 56 Dumbarton Road, Glasgow G11 6NU, UK and
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Gomes-Pereira and D. G. Monckton Chemically induced increases and decreases in the rate of expansion of a CAG{middle dot}CTG triplet repeat Nucleic Acids Res., May 20, 2004; 32(9): 2865 - 2872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Martorell, J. Gamez, M. L. Cayuela, F. K. Gould, J. P. McAbney, T. Ashizawa, D. G. Monckton, and M. Baiget Germline mutational dynamics in myotonic dystrophy type 1 males: Allele length and age effects Neurology, January 27, 2004; 62(2): 269 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Savouret, C. Garcia-Cordier, J. Megret, H. te Riele, C. Junien, and G. Gourdon MSH2-Dependent Germinal CTG Repeat Expansions Are Produced Continuously in Spermatogonia from DM1 Transgenic Mice Mol. Cell. Biol., January 15, 2004; 24(2): 629 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nenguke, M. I. Aladjem, J. F. Gusella, N. S. Wexler, The Venezuela HD Project, and N. Arnheim Candidate DNA replication initiation regions at human trinucleotide repeat disease loci Hum. Mol. Genet., May 1, 2003; 12(9): 1021 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Libby, D. G. Monckton, Y.-H. Fu, R. A. Martinez, J. P. McAbney, R. Lau, D. D. Einum, K. Nichol, C. B. Ware, L. J. Ptacek, et al. Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs are intergenerationally and somatically stable in transgenic mice Hum. Mol. Genet., January 1, 2003; 12(1): 41 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sharma, S. Bhatti, M. Gomez, R. M. Clark, C. Murray, T. Ashizawa, and S. I. Bidichandani The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions Hum. Mol. Genet., September 1, 2002; 11(18): 2175 - 2187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Bacon, M. G. Dunlop, and S. M. Farrington Hypermutability at a poly(A/T) tract in the human germline Nucleic Acids Res., November 1, 2001; 29(21): 4405 - 4413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Rolfsmeier, M. J. Dixon, L. Pessoa-Brandão, R. Pelletier, J. J. Miret, and R. S. Lahue Cis-Elements Governing Trinucleotide Repeat Instability in Saccharomyces cerevisiae Genetics, April 1, 2001; 157(4): 1569 - 1579. [Abstract] [Full Text]
|
|
|
|
 |
|
 E.-K. Tan and T. Ashizawa Genetic Testing in Spinocerebellar Ataxias: Defining a Clinical Role Arch Neurol, February 1, 2001; 58(2): 191 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Sobrido and D. H. Geschwind Molecular Genetics and Inherited Ataxias: Redefining Phenotypes and Pathogenesis Neuroscientist, December 1, 2000; 6(6): 465 - 474. [Abstract] [PDF]
|
|