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

Kim D. Falkenberg, Nancy E. Braverman, Ann B. Moser, Steven J. Steinberg, Femke C.C. Klouwer, Agatha Schlüter, Montserrat Ruiz, Aurora Pujol, Martin Engvall, Karin Naess, Franc Jan van Spronsen, Irene Körver-Keularts, M. Estela Rubio-Gozalbo, Sacha Ferdinandusse, Ronald J.A. Wanders, Hans R. Waterham

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)965-976
Number of pages12
JournalAmerican journal of human genetics
Issue number6
StatePublished - Dec 7 2017


  • PEX1
  • PEX6
  • dominant-negative
  • metabolic
  • peroxisomal disorder
  • peroxisome
  • peroxisome biogenesis disorder

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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