Article Text

PDF
Original article
A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene
  1. Merel S Ebberink1,
  2. Janet Koster1,
  3. Gepke Visser2,
  4. Francjan van Spronsen3,
  5. Irene Stolte-Dijkstra4,
  6. G Peter A Smit3,
  7. Johanna M Fock5,
  8. Stephan Kemp1,
  9. Ronald J A Wanders1,
  10. Hans R Waterham1
  1. 1Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Metabolic Diseases, Wilhelmina Children's Hospital, University of Utrecht, Utrecht, The Netherlands
  3. 3Department of Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  4. 4Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  5. 5Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  1. Correspondence to Dr Hans R Waterham, Laboratory Genetic Metabolic Diseases (F0-222), Academic Medical Center, University of Amsterdam, PO Box 22700, Amsterdam 1100 DE, The Netherlands; h.r.waterham{at}amc.uva.nl

Abstract

Background Peroxisomes are organelles that proliferate continuously and play an indispensable role in human metabolism. Consequently, peroxisomal gene defects can cause multiple, often severe disorders, including the peroxisome biogenesis disorders. Currently, 13 different PEX proteins have been implicated in various stages of peroxisome assembly and protein import. Defects in any of these proteins result in a peroxisome biogenesis disorder. The authors present here a novel genetic defect specifically affecting the division of peroxisomes.

Methods The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11β gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures.

Results The patient presented with congenital cataracts, mild intellectual disability, progressive hearing loss, sensory nerve involvement, gastrointestinal problems and recurrent migraine-like episodes. Although microscopical investigations of patient fibroblasts indicated a clear defect in peroxisome division, all biochemical parameters commonly used for diagnosing peroxisomal disorders were normal. After excluding mutations in all PEX genes previously implicated in peroxisome biogenesis disorders, it was found that the defect was caused by a homozygous non-sense mutation in the PEX11β gene. The peroxisome division defect was exacerbated when the patient's fibroblasts were cultured at 40°C, which correlated with a marked decrease in the expression of PEX11γ.

Conclusions This novel isolated defect in peroxisome division expands the clinical and genetic spectrum of peroxisomal disorders and indicates that peroxisomal defects exist, which cannot be diagnosed by standard laboratory investigations.

  • Peroxisome biogenesis
  • organelle division
  • PEX11
  • Zellweger syndrome spectrum
  • metabolic disorders
  • clinical genetics
  • academic medicine
  • molecular genetics

Statistics from Altmetric.com

Footnotes

  • Funding This work was supported by the “Prinses Beatrix Fonds” Grant Number MAR 03_0216 and by the 6th Framework Program of the European Union Grant Number LSHG-CT-2004-512018.

  • Competing interests None.

  • Patient consent The patient and his parents provided (in Dutch) written informed consent for this study and for publication of the results.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.