title: Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus.
abstract: BACKGROUND
  Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood.
  
  
  OBJECTIVE
  To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA.
  
  
  METHODS
  We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification.
  
  
  RESULTS
  Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group.
  
  
  CONCLUSIONS
  Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.
authors.affiliation: UnIGENe, IBMC, Rua do Campo Alegre 823, 4150-180, Porto, Portugal. isilveir@ibmc.up.pt
authors.forename: I
authors.initials: I
authors.lastname: Silveira
authors.forename: C
authors.initials: C
authors.lastname: Miranda
authors.forename: L
authors.initials: L
authors.lastname: Guimarães
authors.forename: M-C
authors.initials: MC
authors.lastname: Moreira
authors.forename: I
authors.initials: I
authors.lastname: Alonso
authors.forename: P
authors.initials: P
authors.lastname: Mendonça
authors.forename: A
authors.initials: A
authors.lastname: Ferro
authors.forename: J
authors.initials: J
authors.lastname: Pinto-Basto
authors.forename: J
authors.initials: J
authors.lastname: Coelho
authors.forename: F
authors.initials: F
authors.lastname: Ferreirinha
authors.forename: J
authors.initials: J
authors.lastname: Poirier
authors.forename: E
authors.initials: E
authors.lastname: Parreira
authors.forename: J
authors.initials: J
authors.lastname: Vale
authors.forename: C
authors.initials: C
authors.lastname: Januário
authors.forename: C
authors.initials: C
authors.lastname: Barbot
authors.forename: A
authors.initials: A
authors.lastname: Tuna
authors.forename: J
authors.initials: J
authors.lastname: Barros
authors.forename: R
authors.initials: R
authors.lastname: Koide
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
authors.forename: S E
authors.initials: SE
authors.lastname: Holmes
authors.forename: R L
authors.initials: RL
authors.lastname: Margolis
authors.forename: L
authors.initials: L
authors.lastname: Jardim
authors.forename: M
authors.initials: M
authors.lastname: Pandolfo
authors.forename: P
authors.initials: P
authors.lastname: Coutinho
authors.forename: J
authors.initials: J
authors.lastname: Sequeiros
mesh_terms: D000225:Adenine / Q000378:metabolism; D000328:Adult; D000368:Aged; D000483:Alleles; D001938:Brazil; D003596:Cytosine / Q000378:metabolism; D005260:Female; D006147:Guanine / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011174:Portugal; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: D009419:Nerve Tissue Proteins; C095278:atrophin-1; D006147:Guanine; D003596:Cytosine; D000225:Adenine