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Eur J Hum Genet. 2004 Feb;12(2):115-20.

Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder.

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Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, The Netherlands.


The peroxisome biogenesis disorders (PBDs) form a genetically and clinically heterogeneous group of disorders due to defects in at least 11 distinct genes. The prototype of this group of disorders is Zellweger syndrome (ZS), with neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) as milder variants. Liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness are common to PBDs. PBD patients belonging to complementation group 3 (CG3) have mutations in the PEX12 gene, which codes for a protein (PEX12) that contains two transmembrane domains, and a zinc-binding domain considered to be important for its interaction with other proteins of the peroxisomal protein import machinery. We report on the identification of five PBD patients belonging to CG3. Sequence analysis of their PEX12 genes revealed five different mutations, four of which have not been reported before. Four of the patients have mutations that disrupt the translation frame and/or create an early termination codon in the PEX12 open reading frame predicted to result in truncated protein products, lacking at least the COOH-terminal zinc-binding domain. All these patients display the more severe phenotypes (ZS or NALD). The fifth patient expresses two PEX12 alleles capable of encoding a protein that does contain the zinc-binding domain and displayed a milder phenotype (IRD). The three biochemical markers measured in fibroblasts (DHAPAT activity, C26:0 beta-oxidation and pristanic acid beta-oxidation) also correlated with the genotypes. Thus, the genotypes of our CG3 patients show a good correlation with the biochemical and clinical phenotype of the patients.

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