Abstract
BackgroundMutations 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Mutations in PEX1 are the most common primary cause of Zellweger syndrome
Zellweger syndrome (ZS) is caused by mutations in PEX genes, encoding proteins required for the biogenesis of peroxisomes [1,2]
The clinical phenotype and plasma biochemical abnormalities pointed towards a peroxisome biogenesis disorder and PEX1 gene mutations were identified by direct sequencing
Summary
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. Peroxisome biogenesis disorders (PBD, MIM #601539) are a group of autosomal recessive diseases characterized by a severe developmental and metabolic phenotype [1]. ZS is caused by mutations in PEX genes, encoding proteins (peroxins) required for the biogenesis of peroxisomes [1,2]. A downstream complex of two ATPases, PEX1 and PEX6, and the peroxisomal membrane protein PEX26 are thought to mediate recycling of PEX5 into the cytosol [5,6]. This process depends on ubiquitination of PEX5 during the translocation process at the peroxisomal membrane. Models of peroxisome protein import have been reviewed recently [7,8]
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