Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia

Abstract

A novel neurological syndrome has recently been described to be associated with an expanded polyglutamine domain. The expansion results from partial duplication within the TATA-binding protein (TBP). By investigation of 604 sporadic and familial cases with various forms of neurological syndromes and 157 unaffected individuals, we found repeat expansions in the TBP in four patients of two families with autosomal dominant inheritance of ataxia, dystonia, and intellectual decline. Two different genotypes for the repetitive sequence could be demonstrated which led to elongated polyglutamine stretches between 50 and 55 residues, whereas normal alleles with 27 to a maximum of 44 glutamine residues were found in this study. The expansion to 50 or more glutamine residues results in a pathological phenotype and confirms the report of a new polyglutamine disease.

SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6

“…The following sequence analyses revealed just one SCA17 allele with the triplet composition (CAG) 3 (CAA) 3 (CAG) 9 CAA CAG CAA (CAG) 27 CAA CAG coding for 47 glutamine residues.…”

“…10 On the other hand, instability of expanded alleles during transmission could also be demonstrated in hereditary cases. 9 Neurological symptoms in these patients were predominant cerebellar ataxia with variable involvement of pyramidal tracts and basal ganglia.…”

“…9 While normal alleles in the German population contain up to a maximum of 44, pathological alleles associated with clinical symptoms range between 50 and 55 glutamine residues. In addition, we found an allele coding for 48 glutamine residues that was stable inherited but did not cosegregate with the disease phenotype in six siblings.…”

Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17

“…CAG repeat expansion usually occurs in domain IV ranging from 26 to 31, whereas domain II remains normal. 18 -20 Other more complicated patterns have also been observed, such as (CAG) 3 (CAA) 3 (CAG) 9 CAACAGCAA (CAG) 16 CAACAGCAA (CAG) 13 CAACAG and (CAG) 3 (CAA) 3 (CAG) 9 CAACAGCAA (CAG) 9 (CAA) 3 (CAG) 9 CAACAGCAA (CAG) 19 CAACAG. 18,25 This is presumably caused by unequal crossover during recombination.…”

“…They have been reported in German and Italian families. 19,26 It is of note that intergenerational instability and anticipation were documented in these families. Small pool PCR (SP-PCR) is a highly sensitive assay in detecting low levels of somatic mosaicism.…”