title: Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder.
abstract: 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. Common to PBDs are liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness. PBD patients belonging to complementation group 10 (CG10) have mutations in the PEX2 gene (PXMP3), which codes for a protein (PEX2) 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 four PBD patients belonging to CG10. Sequence analysis of their PEX2 genes revealed 4 different mutations, 3 of which have not been reported before. Two of the patients had homozygous mutations leading to truncated proteins lacking both transmembrane domains and the zinc-binding domain. These mutations correlated well with their severe phenotypes. The third patient had a homozygous mutation leading to the absence of the zinc-binding domain (W223X) and the fourth patient had a homozygous mutation leading to the change of the second cysteine residue of the zinc-binding domain (C247R). Surprisingly, the patient lacking the domain had a mild phenotype, whereas the C247R patient had a severe phenotype. This might be due to an increased instability of PEX2 due to the R for C substitution or to a dominant negative effect on interacting proteins.
authors: Lab. Genetic Metabolic Diseases (F0-224), Department of Clinical Chemistry and Peadiatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Jeannette
authors: J
authors: Gootjes
authors: Orly
authors: O
authors: Elpeleg
authors: François
authors: F
authors: Eyskens
authors: Hanna
authors: H
authors: Mandel
authors: Delphine
authors: D
authors: Mitanchez
authors: Noboyuki
authors: N
authors: Shimozawa
authors: Yasuyuki
authors: Y
authors: Suzuki
authors: Hans R
authors: HR
authors: Waterham
authors: Ronald J A
authors: RJ
authors: Wanders
mesh_terms: D001483:Base Sequence; D002459:Cell Fusion; D017931:DNA Primers; D005816:Genetic Complementation Test; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D000074428:Peroxisomal Biogenesis Factor 2; D018901:Peroxisomal Disorders / Q000235:genetics
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; C000614230:PEX2 protein, human; D000074428:Peroxisomal Biogenesis Factor 2