title: DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA.
abstract: BACKGROUND
  Dystonia and parkinsonism may present as part of the same genetic disorder. Identification of the genetic mutations that underlie these diseases may help to shed light on the aetiological processes involved.
  
  
  METHODS
  We identified two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. We did autozygosity mapping and candidate gene sequencing in these families.
  
  
  RESULTS
  High-density genome-wide SNP genotyping revealed a disease-segregating region containing 277 homozygous markers identical by state across all affected members from both families. This novel disease locus, designated DYT16, covers 1.2 Mb at chromosome 2q31.2. The crucial interval contains 11 genes or predicted transcripts. Sequence analysis of every exon of all of these transcripts revealed a single disease-segregating mutation, c.665C>T (P222L), in the stress-response gene PRKRA, which encodes the protein kinase, interferon-inducible double-stranded RNA-dependent activator.
  
  
  CONCLUSIONS
  We describe a mutation within the gene PRKRA that segregates with a novel, autosomal recessive, dystonia parkinsonism syndrome. These patients have progressive, generalised, early-onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia and, in some cases, parkinsonian features, and do not respond to levodopa therapy.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Camargos
authors.forename: Sonja
authors.initials: S
authors.lastname: Scholz
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
authors.forename: Patrick
authors.initials: P
authors.lastname: Lewis
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Catarina Resende
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Francisco
authors.initials: F
authors.lastname: Cardoso
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D004252:DNA Mutational Analysis; D004421:Dystonia / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020734:Parkinsonian Disorders / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D018832:Molecular Chaperones; C104647:PRKRA protein, human; D016601:RNA-Binding Proteins; C108175:TOR1A protein, human