Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder

Am J Hum Genet. 2017 Dec 7;101(6):965-976. doi: 10.1016/j.ajhg.2017.11.007.

Abstract

Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.

Keywords: PEX1; PEX6; dominant-negative; metabolic; peroxisomal disorder; peroxisome; peroxisome biogenesis disorder.

MeSH terms

  • 3' Untranslated Regions / genetics*
  • ATPases Associated with Diverse Cellular Activities / genetics*
  • Alleles
  • Allelic Imbalance / genetics*
  • Cells, Cultured
  • Exome Sequencing
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Peroxisomes / genetics
  • Peroxisomes / pathology
  • Zellweger Syndrome / genetics*

Substances

  • 3' Untranslated Regions
  • ATPases Associated with Diverse Cellular Activities
  • PEX6 protein, human