Beyond the Qs in the polyglutamine diseases

  1. Harry T. Orr
  1. Departments of Laboratory Medicine and Pathology, Genetics, Cell Biology and Development, Biochemistry, Molecular Biology and Biophysics, and Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA

This extract was created in the absence of an abstract.

It was 10 years ago that Kurt Fischbeck and his colleagues (La Spada et al. 1991) reported the identification of a novel mutational mechanism that altered the sequence of a protein: the addition of glutamines to a polyglutamine tract within the androgen receptor (AR). This mutation occurred in individuals affected with the motor neuron disease spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease. With the cloning of the genes affected in Huntington disease (HD; Huntington's Disease Collaborative Research Group 1993) and spinocerebellar ataxia type 1 (SCA1; Orr et al. 1993), and subsequently with the identification of the basis for several other neurodegenerative diseases (for review, see Zoghbi and Orr 2000), it has become apparent that an expansion of a polyglutamine tract is the mutational mechanism underlying several neurodegenerative diseases. Currently, this group of disorders consists of eight diseases (Table1). At the DNA level, the polyglutamine diseases are result from the expansion of an unstable CAG triplet repeat, placing the polyglutamine diseases within a broader class of inherited disorders, the unstable trinucleotide repeat diseases (Warren 1996).

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Table 1.

Polyglutamine diseases

With the identification of trinucleotide repeat and polyglutamine expansions as disease-causing mutational mechanisms, two general questions arose. What are the mechanisms for the repeat instability at the DNA level, and what are the effects of polyglutamine expansion at the protein level? A discussion of the genetic mechanism of repeat instability is beyond the scope of this review (see McMurray 1999). The purpose of this review is to summarize information that has accumulated with regard to the effects of polyglutamine expansion at the protein level. Focusing on SCA1, HD, and SCA6, an attempt will be made to identify important insights into the pathogenic mechanisms of these intriguing disorders.

One might envisage two possible mechanisms for the pathogenic effects of an expanded polyglutamine …

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