Mutation at the SCA17 locus is not a common cause of parkinsonism

Abstract

Spinocerebellar ataxia (SCA) 17 is a dominant, progressive, neurodegenerative disorder. The disease is caused by a triplet repeat expansion mutation within TATA-binding protein (TBP). Ataxia, dementia, parkinsonism and dystonia are common features.

We have previously shown in several pedigrees that SCA-2 and SCA-3 can cause both parkinsonism and typical Parkinson's disease in the absence of prominent ataxia; a finding which has been confirmed by others.

Given these previous findings and the description of parkinsonism as a common feature of SCA-17 we examined this locus in a series of probands from families with 2 or more members affected with parkinsonism (n=51) and a group of sporadic parkinsonism patients (n=59). We did not find any repeat sizes in the pathogenic range. The repeats we observed ranged from 29 to 41 (mean 36.8; median 37).

We conclude that SCA-17 repeat expansion mutations are not a common cause of familial parkinsonism.

Introduction

The spinocerebellar ataxias (SCAs) represent a family of genetically heterogeneous dominant neurodegenerative disorders defined by progressive ataxia resulting from the degeneration of cerebellar and spinal systems.

The gene mutations responsible for SCA-1, -2, -3, -6, -7, -8, -10, -12, -17 and dentatorubral pallidoluysian atrophy (DRPLA) have been identified [1], [2], [3], [4]. Of these disorders SCA-1, -2, -3, -6, -7, -17 and DRPLA are caused by expansion of CAG trinucleotide repeat regions [5], [6]. These expansions are translated into polyglutamine (polyQ) tracts within the protein product. SCA-8, -10 and -12 are caused by non-coding repeat expansions [2], [4], [7]. There is no obvious functional relationship between the genes mutated in these disorders suggesting that the expansion mutations may be responsible for both the pathogenesis and pathoetiology of these diseases.

The clinical phenotype of the SCAs is variable but consists of some common features, most notably progressive ataxia. There is a direct relationship between repeat length and severity of disease in several forms of SCA [8]. The mechanism of mutation results in intergenerational instability of the repeat that, in turn, leads to the observation of anticipation in some but not all SCA families.

TATA binding protein (TBP), located on chromosome 6 at 6q27 is a transcription initiation factor containing a mixed CAG/CAA repeat encoding a polyglutamine tract. Expansion of the polyglutamine encoding repeat was first implicated as a cause of a progressive neurodegenerative disease in a Japanese female [9]. Expansion of the normal allele, ranging in size from 29 to 42 repeats, to a repeat size of between 47 and 63 glutamine encoding units was subsequently linked to a disorder characterized by ataxia and cognitive decline [1], [10], [11]. In addition to these progressive neurodegenerative symptoms the majority of SCA17 patients also exhibit dystonia and/or parkinsonism [11].

We and others have previously described families with SCA-2 and SCA-3 expansion mutations presenting with predominant parkinsonian symptoms and in some cases typical Parkinson's disease [12], [13], [14], [15]. Here we test the hypothesis that SCA17 expansion mutations, which have been associated with parkinsonism, may be a cause of disease in families with a history of parkinsonism in the absence of any obvious ataxia. We have analyzed the SCA17 repeat in probands from 51 families with a positive history for Parkinson's disease or parkinsonism. We have analyzed this repeat in 59 sporadic cases of parkinsonism in an attempt to define if de novo expansions may cause parkinsonism. Based on our previous finding that SCA mutations may present with parkinsonism when expressed on the background of an ethnic African or Asian-origin persons genome; 51% of these samples were from non-Caucasian parkinsonism patients.