title: Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain.
abstract: OBJECTIVE
  To identify SORL1 risk genotypes that determine receptor protein expression in the human brain.
  
  
  METHODS
  DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively.
  
  
  METHODS
  Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank.
  
  
  METHODS
  Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease.
  
  
  RESULTS
  Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein.
  
  
  CONCLUSIONS
  Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.
authors.affiliation: Max-Delbrück Center for Molecular Medicine, Robert-Röessle-Strasse 10, Berlin, Germany.
authors.forename: Safak
authors.initials: S
authors.lastname: Caglayan
authors.forename: Anja
authors.initials: A
authors.lastname: Bauerfeind
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schmidt
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Carlo
authors.forename: Thaneas
authors.initials: T
authors.lastname: Prabakaran
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001344:Autopsy; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012313:RNA / Q000235:genetics; D018570:Risk Assessment
chemical_list: D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human; D012313:RNA; D004247:DNA