An expanded CAG repeat sequence in spinocerebellar ataxia type 7. (original) (raw)

  1. K Lindblad,
  2. M L Savontaus,
  3. G Stevanin,
  4. M Holmberg,
  5. K Digre,
  6. C Zander,
  7. H Ehrsson,
  8. G David,
  9. A Benomar,
  10. E Nikoskelainen,
  11. Y Trottier,
  12. G Holmgren,
  13. L J Ptacek,
  14. A Anttinen,
  15. A Brice, and
  16. M Schalling
  17. Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. keli@gen.ks.se

Abstract

Expanded CAG repeat sequences have been identified in the coding region of genes mutated in several neurodegenerative disorders, including spinocerebellar ataxia type 1 and Machado-Joseph disease. In all disorders described to date the CAG expansion codes for an elongated polyglutamine chain. An increased polyglutamine chain size leads to a more severe disease, thus correlating with the genetic anticipation seen in repeat expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar ataxia with anticipation and a progressive degeneration of the cerebellar cortex. Using repeat expansion detection (RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, we have analyzed 8 SCA7 families for the presence of CAG repeat expansions. RED products of 150-240 bp were found in all affected individuals and found to cosegregate with the disease (P < 0.000001, n = 66), indicating strongly that a CAG expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease, we were able to estimate the average expansion size in SCA7 to be 64 CAG copies.

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