title: Characterization of two common 5' polymorphisms in PEX1 and correlation to survival in PEX1 peroxisome biogenesis disorder patients.
abstract: BACKGROUND
  Mutations in PEX1 are the most common primary cause of Zellweger syndrome. In addition to exonic mutations, deletions and splice site mutations two 5' polymorphisms at c.-137 and c.-53 with a potential influence on PEX1 protein levels have been described in the 5' untranslated region (UTR) of the PEX1 gene.
  
  
  METHODS
  We used RACE and in silico promoter prediction analysis to study the 5' UTR of PEX1. We determined the distribution of PEX1 5' polymorphisms in a cohort of 30 Zellweger syndrome patients by standard DNA sequencing. 5' polymorphisms were analysed in relation to the two most common mutations in PEX1 and were incorporated into a novel genotype-phenotype analysis by correlation of three classes of PEX1 mutations with patient survival.
  
  
  RESULTS
  We provide evidence that the polymorphism 137 bp upstream of the ATG codon is not part of the UTR, rendering it a promoter polymorphism. We show that the first, but not the second most common PEX1 mutation arose independently of a specific upstream polymorphic constellation. By genotype-phenotype analysis we identified patients with identical exonic mutation and identical 5' polymorphisms, but strongly differing survival.
  
  
  CONCLUSIONS
  Our study suggests that two different types of PEX1 5' polymorphisms have to be distinguished: a 5' UTR polymorphism at position c.-53 and a promoter polymorphism 137 bp upstream of the PEX1 start codon. Our results indicate that the exonic PEX1 mutation correlates with patient survival, but the two 5' polymorphisms analysed in this study do not have to be considered for diagnostic and/or prognostic purposes.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, University of Göttingen, Robert Koch Str, 40, 37099 Göttingen, Germany. sven.thoms@med.uni-goettingen.de
authors.forename: Sven
authors.initials: S
authors.lastname: Thoms
authors.forename: Sabine
authors.initials: S
authors.lastname: Grønborg
authors.forename: Jana
authors.initials: J
authors.lastname: Rabenau
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohlenbusch
authors.forename: Hendrik
authors.initials: H
authors.lastname: Rosewich
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
mesh_terms: D020121:5' Untranslated Regions; D000074183:ATPases Associated with Diverse Cellular Activities; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D015211:Zellweger Syndrome / Q000235:genetics* / Q000401:mortality
chemical_list: D020121:5' Untranslated Regions; D008565:Membrane Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human