Brain, Vol. 124, No. 10, 1939-1947,
October 2001
© 2001 Oxford University Press
CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia
1 INSERM U289, 2 Fédération de Neurologie and 3 Départment de Génétique, Cytogénétique et Embryologie, Hôpital de la Salpêtrière, Paris, France, 4 Laboratory of Neuropathology, Born-Bunge Foundation, 5 Department of Neurology and Memory Clinic, Middelheim Hospital and University of Antwerp, 6 Department of Molecular Genetics, Flanders Interuniversity, Institute for Biotechnology,Born-Bunge Foundation, University of Antwerp, Antwerp, Belgium and 7 Department of Neurology, Hôpital Fontmaure, Clermont-Ferrand, France
Correspondence to:
Dr Alexis Brice, INSERM U 289, Hôpital de la Salpêtrière, 47, boulevard de l'Hôpital, 75651 Paris, Cedex 13, France E-mail: brice{at}ccr.jussieu.fr
At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.
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