title: Mutation in ADORA1 identified as likely cause of early-onset parkinsonism and cognitive dysfunction.
abstract: We aimed to identify the genetic cause of neurological disease in an Iranian family whose manifestations include symptoms of parkinsonism and cognitive dysfunction.
  
  
  
  Clinical data on the patients were gathered by interviews with parents, neurological examinations, and laboratory tests. Genetic analysis was performed by genome-wide single-nucleotide polymorphism homozygosity mapping and exome sequencing. The effect of putative disease-causing mutation was assessed by immunocytochemistry on HEK293 cells and Western blotting on proteins extracted from HEK293 cells transfected with wild-type and mutated genes.
  
  
  
  Homozygosity mapping and exome sequencing led to identification of a mutation in ADORA1 that causes p.Gly279Ser in the encoded protein, adenosine A1 receptor (A1 R), as the probable cause of disease. The mutation segregated with disease status in the family, affects a highly conserved amino acid, and was absent in 700 controls.
  
  
  
  The known biological activities of A1 R in brain functions including its physical interaction with and inhibitory effect on dopamine receptor D1 provide supportive evidence that disruptions of A1 R may result in neurological dysfunction. Also, recent evidence on the related adenosine A2B receptor marks the domain in which the mutation is positioned as important for function. Finally, ADORA1 is located within the Parkinson's disease locus PARK16, which has been identified in several populations. ADORA1 may be the PD susceptibility gene within this locus. The molecular mechanism by which p.Gly279Ser disrupts A1 R function remains unknown, but a quantitative effect on interaction with the dopamine receptor was not shown. © 2016 International Parkinson and Movement Disorder Society.
authors.affiliation: School of Biology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Jaberi
authors.affiliation: Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Rohani
authors.affiliation: Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Gholam Ali
authors.initials: GA
authors.lastname: Shahidi
authors.affiliation: Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Nafissi
authors.affiliation: School of Biology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Arefian
authors.affiliation: School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Masoud
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: School of Biology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Moghadam
authors.affiliation: Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Mohsen Karimi
authors.initials: MK
authors.lastname: Arzenani
authors.affiliation: Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Farid
authors.initials: F
authors.lastname: Keramatian
authors.affiliation: Illumina, San Diego, California, USA.
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.affiliation: Illumina, San Diego, California, USA.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Illumina, San Diego, California, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Turk
authors.affiliation: Illumina, San Diego, California, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Steemers
authors.affiliation: School of Biology, College of Science, University of Tehran, Tehran, Iran.|Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Elahe
authors.initials: E
authors.lastname: Elahi
mesh_terms: D000328:Adult; D060825:Cognitive Dysfunction / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007492:Iran; D008297:Male; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D043682:Receptor, Adenosine A1 / Q000235:genetics*
chemical_list: D043682:Receptor, Adenosine A1
keywords: ADORA1; cognitive dysfunction; dopamine receptor D1; exome sequencing; parkinsonism