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.

Kim D Falkenberg ¹, Nancy E Braverman ², Ann B Moser ³, Steven J Steinberg ⁴, Femke C C Klouwer ⁵, Agatha Schlüter ⁶, Montserrat Ruiz ⁶, Aurora Pujol ⁷, Martin Engvall ⁸, Karin Naess ⁹, FrancJan van Spronsen ¹⁰, Irene Körver-Keularts ¹¹, M Estela Rubio-Gozalbo ¹², Sacha Ferdinandusse ¹, Ronald J A Wanders ¹, Hans R Waterham ¹³

Affiliations

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: h.r.waterham@amc.uva.nl.

PMID: 29220678 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.

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