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Human Genetics

, Volume 99, Issue 5, pp 692-695

Identification of an HD patient with a (CAG)180 repeat expansion and the propagation of highly expanded CAG repeats in lambda phage

  • Kirupa SathasivamAffiliated withMedical and Molecular Genetics, UMDS, 8th Floor Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK Fax: +44-171-955-4644
  • , Iheoma AmaechiAffiliated withMedical and Molecular Genetics, UMDS, 8th Floor Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK Fax: +44-171-955-4644
  • , Laura MangiariniAffiliated withMedical and Molecular Genetics, UMDS, 8th Floor Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK Fax: +44-171-955-4644
  • , G. BatesAffiliated withMedical and Molecular Genetics, UMDS, 8th Floor Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK Fax: +44-171-955-4644

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Abstract

The Huntington’s disease mutation has been identified as a CAG/polyglutamine repeat expansion in a large gene of unknown function. In order to develop the transgenic systems necessary to uncover the molecular pathology of this disorder, it is necessary to be able to manipulate highly expanded CAG repeats in a cloned form. We have identified a patient with an expanded allele of greater than 170 repeat units and have cloned the mutant allele in the lambda zap vector. The recovery of highly expanded repeats after clone propagation was more efficient when repeats were maintained as lambda phage clones rather than as the plasmid counterparts. Manipulation of the repeats as phage clones has enabled us to generate Huntington’s disease transgenic mice that contain highly expanded (CAG)115–(CAG)150 repeats and that develop a progressive neurological phenotype.