Sca1. Phenotype-Genotype Correlation Studies

ã 2002 Nature Publishing Group

European Journal of Human Genetics (2002) 10, 204 ± 209
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ARTICLE

Spinocerebellar ataxia type 1 (SCA1): Phenotype-genotype correlation studies in intermediate alleles
È Christine Zuhlke*,1, Andreas Dalski1,4, Yorck Hellenbroich1,4, Stefanie Bubel2, È Eberhard Schwinger1 and Katrin Burk3
Èbeck,Lu Èbeck, Germany; 2Department of Neurology, University of Institute of Human Genetics, University of Lu 3 Èbingen, Tu Èbingen, Germany Èbeck, Lu Èbeck, Germany; Department of Neurology, University of Tu Lu CAG repeat expansions with loss of CAT interruptions in the coding region of the ataxin-1 gene are associated with spinocerebellar ataxia type 1 (SCA1). For molecular genetic diagnosis it isnecessary to define the limits of normal and pathological size ranges. In most studies, normal alleles as measured by PCR range from 6 ± 39 units with interruptions of 1 ± 3 CAT trinucleotides that are thought to be involved in the stability of the trinucleotide stretch during DNA replication. Expanded alleles have been reported to carry 39 ± 81 CAG trinucleotides without stabilising CATinterruptions. To evaluate the limits between normal and disease size ranges we analysed the repeat length and composition of the SCA1 gene in 15 individuals with alleles ranging from 36 and 41 triplets for genotype-phenotype correlation studies. We found the 39 trinucleotide-allele to be either interrupted by CAT repeats or formed by a pure CAG stretch. The clinical features of individuals carrying 39uninterrupted CAG repeats did not differ from the SCA1 phenotype in general with dysphagia, pale discs, pyramidal signs and cerebellar tremor being more frequent as compared to other SCA genotypes. In contrast, the interrupted 39 trinucleotide-allele is not correlated with the SCA1 phenotype. European Journal of Human Genetics (2002) 10, 204 ± 209. DOI: 10.1038/sj/ejhg/5200788 Keywords: SCA1;intermediate allele; repeat expansion; interruption
1

Introduction

The spinocerebellar ataxias (SCAs) are autosomal dominant progressive neurodegenerative disorders displaying clinical and genetic heterogeneity. The loci and mutations associated with at least eight subtypes of SCAs have been cloned: SCA11 (MIM 164400), SCA2 2 ± 4 (MIM 183090), SCA35 (MIM 109150), SCA66 (MIM 183086), SCA77 (MIM164500), SCA88 (MIM 603680), SCA109 (MIM 603516), SCA1210 (MIM 604326). Furthermore, mutations in the DRPLA gene11,12 (MIM 125370) and the TBP/SCA17 gene13 ± 15

È *Correspondence: Christine Zuhlke, Institute of Human Genetics, È È University of Lubeck, Ratzeburger Allee 160, D-23538 Lubeck, Germany Tel: +49 451 500 2621; Fax: +49 451 500 4187; E-mail: zuehlke@medinf.mu-luebeck.de 4 A Dalski and YHellenbroich contributed equally to this work. Received 23 July 2001; revised 15 January 2002; accepted 24 January 2002

(MIM 600075) produce SCA-like phenotypes. In these disorders, expansions of unstable nucleotide repeats in the respective genes are implicated in the pathogenesis of the disease. Unstable expansions of trinucleotide repeats have been shown to cause at least 14 neurologicaldiseases (for review).16 Spinocerebellar ataxia type 1 (SCA1) primarily affects the brainstem, spinocerebellar tracts and cerebellar Purkinje cells. Patients with SCA1 develop progressive ataxia of limb and gait, as well as bulbar and pyramidal symptoms. In most cases, there is evidence for fronto-executive dysfunction while general intellectual impairment is restricted to advanced stages of thedisease.17,18 The neurodegenerative process in SCA1 is thought to be contingent on transcription and translation of expanded CAG trinucleotide repeats within the coding region of the gene. This results in the synthesis of a pathologically altered

Intermediate SCA1 alleles C Zuhlke et al È
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gene product harbouring an expanded polyglutamine stretch.1 Normal SCA1 alleles range from 6 ± 39...