title: Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2.
abstract: The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which - like CAG codons - code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.
authors.affiliation: Memory Disorders Research Group, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Tua
authors.initials: T
authors.lastname: Vinther-Jensen
authors.forename: Jakob
authors.initials: J
authors.lastname: Ek
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.forename: Flemming
authors.initials: F
authors.lastname: Skovby
authors.forename: Lena E
authors.initials: LE
authors.lastname: Hjermind
authors.forename: Jørgen E
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Troels Tolstrup
authors.initials: TT
authors.lastname: Nielsen
mesh_terms: D000293:Adolescent; D000067528:Ataxins; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D059010:Single-Cell Analysis; D013094:Spermatozoa / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D013132:Spinocerebellar Degenerations / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins