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.
- 1. Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
- 2. Department of Pediatrics and Human Genetics, Research Institute of the McGill University Health Center and McGill University, Montreal, QC H4A 3J1, Canada.
- 3. Kennedy Krieger Institute, Baltimore, MD 21205, USA.
- 4. Institute of Genetic Medicine and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- 5. Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Pediatric Neurology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
- 6. Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL, Barcelona 08908, Spain; CIBERER U759, Center for Biomedical Research on Rare Diseases, Valencia 46010, Spain.
- 7. Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL, Barcelona 08908, Spain; CIBERER U759, Center for Biomedical Research on Rare Diseases, Valencia 46010, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona 08010, Spain.
- 8. Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 171 77, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 76, Sweden.
- 9. Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 171 77, Sweden; Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, Stockholm 171 77, Sweden.
- 10. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen 9700 RB, the Netherlands.
- 11. Department of Pediatrics, Maastricht University Medical Center, Maastricht 6211 LK, the Netherlands.
- 12. Department of Pediatrics, Maastricht University Medical Center, Maastricht 6211 LK, the Netherlands; Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht 6211 LK, the Netherlands.
- 13. Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address: [email protected].
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.