title: Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions.
abstract: Trinucleotide repeat disorders are a heterogeneous group of diseases caused by the expansion, beyond a pathogenic threshold, of unstable DNA tracts in different genes. Sequence interruptions in the repeats have been described in the majority of these disorders and may influence disease phenotype and heritability. Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by a CAG trinucleotide expansion in the androgen receptor (AR) gene. Diagnostic testing and previous research have relied on fragment analysis polymerase chain reaction to determine the AR CAG repeat size, and have therefore not been able to assess the presence of interruptions. We here report a sequencing study of the AR CAG repeat in a cohort of SBMA patients and control subjects in the United Kingdom. We found no repeat interruptions to be present, and we describe differences between sequencing and traditional sizing methods.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London, UK. Electronic address: p.fratta@prion.ucl.ac.uk.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.forename: Toby
authors.initials: T
authors.lastname: Collins
authors.forename: Sally
authors.initials: S
authors.lastname: Pemble
authors.forename: Suran
authors.initials: S
authors.lastname: Nethisinghe
authors.forename: Anny
authors.initials: A
authors.lastname: Devoy
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
mesh_terms: D015331:Cohort Studies; D006801:Humans; D020966:Muscular Disorders, Atrophic / Q000175:diagnosis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D006113:United Kingdom
chemical_list: D011944:Receptors, Androgen
keywords: CAG; Interruptions; Kennedy's disease; Spinal bulbar muscular atrophy; Trinucleotide
references.citation: Nat Genet. 1996 Nov;14(3):269-76
references.pmid: 8896555
references.citation: Nature. 1991 Jul 4;352(6330):77-9
references.pmid: 2062380
references.citation: Nat Genet. 1995 Jul;10(3):344-50
references.pmid: 7670474
references.citation: Nat Genet. 1993 Jul;4(3):221-6
references.pmid: 8358429
references.citation: Hum Mol Genet. 1999 Oct;8(11):2047-53
references.pmid: 10484774
references.citation: J Med Genet. 1999 Jul;36(7):546-8
references.pmid: 10424816
references.citation: Cell. 1993 Mar 26;72(6):971-83
references.pmid: 8458085
references.citation: Nat Genet. 1994 Nov;8(3):221-8
references.pmid: 7874163
references.citation: Nat Genet. 1994 Jan;6(1):9-13
references.pmid: 8136840
references.citation: PLoS One. 2011 Mar 29;6(3):e17951
references.pmid: 21479228
references.citation: Nat Genet. 1993 Nov;5(3):254-8
references.pmid: 8275090
references.citation: Annu Rev Neurosci. 2007;30:575-621
references.pmid: 17417937
references.citation: Brain. 2006 Jun;129(Pt 6):1446-55
references.pmid: 16621916
references.citation: PLoS Genet. 2013;9(7):e1003648
references.pmid: 23935513