LETTERS TO JMG

Identification of a novel PEX14 mutation in Zellweger syndrome

S J Huybrechts¹, P P Van Veldhoven¹, I Hoffman², R Zeevaert², R de Vos³, P Demaerel³, M Brams¹, J Jaeken², M Fransen¹, D Cassiman²

¹ Katholieke Universiteit Leuven, Faculteit Geneeskunde, Departement Moleculaire Celbiologie, LIPIT, Campus Gasthuisberg (O&N 1), Leuven, Belgium
² Katholieke Universiteit Leuven, Faculteit Geneeskunde, Departement Vrouw & Kind, UZ Leuven, Belgium
³ Katholieke Universiteit Leuven, Faculteit Geneeskunde, Departement Medisch Diagnostische Wetenschappen, UZ Leuven, Belgium

Dr Marc Fransen, Campus Gasthuisberg O&N1, Herestraat 49 box 601, B-3000 Leuven, Belgium; marc.fransen{at}med.kuleuven.be

Background: Peroxisome biogenesis disorders are a clinically and genetically heterogeneous group of very severe autosomal recessive disorders caused by impaired peroxisome biogenesis. The prototype of this group of disorders is the cerebro-hepato-renal syndrome of Zellweger.

Methods and results: Here we report a patient with Zellweger syndrome, who presented at the age of 3 months with icterus, dystrophy, axial hypotonia, facial dysmorphy, posterior embryotoxon, and hepatomegaly. Abnormal findings of metabolic screening tests included hyperbilirubinaemia, hypoketotic dicarboxylic aciduria, increased C_26:0 and decreased C_22:0 plasma levels, and strongly reduced plasmalogen concentrations. In fibroblasts, both peroxisomal - and β-oxidation were impaired. Liver histology revealed bile duct paucity, cholestasis, arterial hyperplasia, very small branches of the vena portae, and parenchymatic destruction. Immunocytochemical analysis of cultured fibroblasts demonstrated that the cells contain peroxisomal remnants lacking apparent matrix protein content and PEX14, a central membrane component of the peroxisomal matrix protein import machinery. Transfection of fibroblasts with a plasmid coding for wild-type PEX14 restored peroxisomal matrix protein import, indicating that the primary genetic defect affecting the patient is indeed linked to PEX14. Mutational analysis of this gene revealed a genomic deletion leading to the deletion of exon 3 from the coding DNA (c.85-?_170+?del) and a concomitant change of the reading frame (p.[Ile29_Lys56del;Gly57GlyfsX2]).

Conclusions: This report represents the second PEX14-deficiency associated with Zellweger syndrome and the first documentation of a PEX14-deficient patient with detailed clinical follow-up and biochemical, morphological, and radiological data.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Grou, C. P., Carvalho, A. F., Pinto, M. P., Huybrechts, S. J., Sa-Miranda, C., Fransen, M., Azevedo, J. E. (2009). Properties of the Ubiquitin-Pex5p Thiol Ester Conjugate. J. Biol. Chem. 284: 10504-10513 [Abstract] [Full Text]