Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders.
Peroxisome biogenesis disorders, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease, are lethal hereditary diseases caused by abnormalities in peroxisomal assembly. To date, 12 genotypes have been identified. We now have evidence that the complete human cDNA encoding Pex13p, an SH3 protein of a docking factor for the peroxisome targeting signal 1 receptor (Pex5p), rescues peroxisomal matrix protein import and its assembly in fibroblasts from PBD patients of complementation group H. In addition, we detected mutations on the human PEX13 cDNA in two patients of group H. A severe phenotype of a ZS patient (H-02) was homozygous for a nonsense mutation, W234ter, which results in the loss of not only the SH3 domain but also the putative transmembrane domain of Pex13p. A more mildly affected NALD patient (H-01), whose fibroblasts showed the temperature-sensitive (TS) phenotype, was homozygous for a missense mutation in the SH3 domain of Pex13p, I326T. This mutant PEX13 cDNA expression in a PEX13-defective CHO mutant showed I326T to be a TS mutation and thus suggested that Pex13p with the I326T mutation in the SH3 domain is stable at 30 degrees C but is somewhat unstable at 37 degrees C.
Shimozawa
N
N
Department of Pediatrics, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8076, Japan. nshim@cc.gifu-u.ac.jp
Suzuki
Y
Y
Zhang
Z
Z
Imamura
A
A
Toyama
R
R
Mukai
S
S
Fujiki
Y
Y
Tsukamoto
T
T
Osumi
T
T
Orii
T
T
Wanders
R J
RJ
Kondo
N
N
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008830:Microbodies / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D018901:Peroxisomal Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074435:Peroxisome-Targeting Signal 1 Receptor; D010641:Phenotype; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015211:Zellweger Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D008565:Membrane Proteins; C101884:PEX13 protein, human; D000074435:Peroxisome-Targeting Signal 1 Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D004247:DNA