title: T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease.
abstract: BACKGROUND
  To date, 5 well-confirmed genes for Parkinson disease (PD) have been identified, including 3 autosomal recessive genes: PTEN-induced putative kinase 1 (PINK1), parkin, and DJ-1. Almost nothing is known about the genetics of PD in Saudi Arabia; however, consanguineous families, not infrequent in this population, could be important in the evaluation of known PD genes and the search for new PD factors in the future.
  
  
  OBJECTIVE
  To investigate known recessive PD genes in 5 consanguineous Saudi families with PD.
  
  
  METHODS
  The entire open frame as well as the untranslated region and all 5' and 3' intron-exon boundaries of the PINK1, parkin, and DJ-1 genes were sequenced in 5 probands in Saudi families.
  
  
  RESULTS
  Four of 5 probands tested negative for PINK1, parkin, and DJ-1 mutations. However, in a large Saudi family with PD with at least 3 consanguineous marriages between first cousins, we detected a threonine to methionine substitution at codon 313 (T313M) PINK1 mutation that affected the kinase domain. Manifestations of the disease in this family included early onset (age, 28-38 years), tremulous movement, slow progression, diurnal fluctuations, bradykinesia, good response to levodopa therapy, and only mild dyskinesias. A neurologist blinded to genetic status clinically evaluated 15 family members, all older than 20 years, and diagnosed PD only in individuals who were later found to be homozygous for the T313M mutation. None of the 13 heterozygotes demonstrated any sign of PD.
  
  
  CONCLUSIONS
  A homozygous T313M mutation is responsible for PD in this large Saudi family. However, the heterozygous T313M mutation does not act as a PD susceptibility factor, which is in contrast to several reports of mutations affecting only 1 PINK1 allele discovered in sporadic PD.
authors.affiliation: Departments of Comparative Medicine and Neuroscience, and Aragene Laboratory, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. m.chishti@utoronto.ca
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Chishti
authors.forename: Saeed
authors.initials: S
authors.lastname: Bohlega
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Arslan
authors.initials: A
authors.lastname: Loualich
authors.forename: Pamela
authors.initials: P
authors.lastname: Carroll
authors.forename: Christine
authors.initials: C
authors.lastname: Sato
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D012529:Saudi Arabia / Q000453:epidemiology; D016896:Treatment Outcome; D000099202:PTEN-Induced Putative Kinase
chemical_list: D007980:Levodopa; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase