Original Article Small de novo duplication in the repeat region of the TATA-box-binding protein gene manifest with a phenotype similar to variant Creutzfeldt-Jakob disease A Shatunov a , EA Fridman a , FI Pagan a , J Leib a , A Singleton b , M Hallett a and LG Goldfarb a a National Institute of Neurological Disorders and Stroke, and b National Institute on Aging, National Institutes of Health, Rockville Pike, Bethesda, MD, USA Key words: DNA rearrangement – insertion/duplication – spinocerebellar ataxia – TATA-box binding protein – variant Creutzfeldt-Jakob disease Corresponding author: Lev G. Goldfarb, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 4B37, Bethesda, MD 20892-1361, USA. Tel.: þ1 301 402 1480; fax: þ1 301 496 6341; e-mail: goldfarbl@ninds.nih.gov Received 14 May 2004, revised and accepted for publication 3 August 2004 Shatunov A, Fridman EA, Pagan FL, Leib J, Singleton A, Hallett M, Goldfarb LG. Small de novo duplication in the repeat region of the TATA-box-binding protein gene manifest with a phenotype similar to variant Creutzfeldt-Jakob disease. Clin Genet 2004: 66: 496–501. # Blackwell Munksgaard, 2004 A 20-year-old North American patient developed rapidly progressive cognitive decline and pronounced ataxia, a phenotype compatible with prion disease. No structural changes were found in the PRNP gene, which excludes genetic prion disease, but the patient’s PRNP codon 129 Met/Met genotype is known to predispose to variant Creutzfeldt-Jakob disease (vCJD). Further studies identified an expanded allele with 55 CAG/CAA repeats in the TBP gene. The increase of trinucleotide repeat number in the coding region of the TBP gene has previously been associated with spinocerebellar ataxia type 17 (SCA17). The patient’s unaffected parents and siblings show normal-size TBP alleles with 37–38 repeats. Haplotype and nucleotide sequence analyses clearly indicate that the mutation has occurred de novo on a paternal chromosome by insertion/ duplication of a (CAA)(CAG)(CAA)(CAG) 15 sequence. This report presents a second fully investigated sporadic case of SCA17 occurring as a result of a DNA rearrangement within the polymorphic TBP trinucleotide repeat region. Our findings suggest that patients suspected of vCJD should undergo testing for SCA17, Huntington’s disease and other neurodegener- ative disorders having phenotypic similarities with vCJD. Expansion of unstable trinucleotide repeats has been recognized as the cause of well-outlined neuro- degenerative disorders, including Huntington’s disease and spinocerebellar ataxias. Triplet repeat expansion in the TBP gene has recently been associated with SCA17 (1). TBP is a general transcription initiation factor that regulates the expression of many genes. A polyglutamine domain coded by the CAG/CAA repeat is located in the N-terminus of TBP. The normal number of glutamine residues is in the 25–43 range, whereas SCA17 patients show an increase to 45–63 resi- dues (1–3). At the gene level, the repeat region is composed of recognizable alternating CAG/ CAA-containing elements and is extremely poly- morphic even in normal chromosomes (4). The complex architecture of the repeat region enables tracing intergenerational transmissions. The elong- ated TBP chromosomes do not show meiotic instability (2, 5, 6) as generally seen in other SCA genes. SCA17 prevalence among other SCAs is 0.3–3% (2, 7), i.e. approximately 1 : 10 7 in the general population. The frequency of a de novo generated CAG/CAA expansion in the TBP gene must, therefore, be extremely rare, perhaps close to one per billion. Analysis of how de novo alleles have been generated may help us under- stand the mechanisms of gene rearrangements and parent-of-origin effects (8). Methods We evaluated a patient, who developed cognitive impairment, gait imbalance, worsening handwriting, Clin Genet 2004: 66: 496–501 Copyright # Blackwell Munksgaard 2004 Printed in Denmark. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2004.00356.x 496