Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D.
Peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome (ZS), are autosomal recessive diseases caused by a deficiency in peroxisome assembly as well as by a malfunction of peroxisomes, among which>10 genotypes have been identified. We have isolated a human PEX16 cDNA (HsPEX16) by performing an expressed-sequence-tag homology search on a human DNA database, by using yeast PEX16 from Yarrowia lipolytica and then screening the human liver cDNA library. This cDNA encodes a peroxisomal protein (a peroxin Pex16p) made up of 336 amino acids. Among 13 peroxisome-deficiency complementation groups (CGs), HsPEX16 expression morphologically and biochemically restored peroxisome biogenesis only in fibroblasts from a CG-D patient with ZS in Japan (the same group as CG-IX in the United States). Pex16p was localized to peroxisomes through expression study of epitope-tagged Pex16p. One patient (PBDD-01) possessed a homozygous, inactivating nonsense mutation, C-->T at position 526 in a codon (CGA) for 176Arg, that resulted in a termination codon (TGA). This implies that the C-terminal half is required for the biological function of Pex16p. PBDD-01-derived PEX16 cDNA was defective in peroxisome-restoring activity when expressed in the patient's fibroblasts. These results demonstrate that mutation in PEX16 is the genetic cause of CG-D PBDs.
Honsho
M
M
Department of Biology, Faculty of Science, Kyushu University, Fukuoka, Japan.
Tamura
S
S
Shimozawa
N
N
Suzuki
Y
Y
Kondo
N
N
Fujiki
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D004252:DNA Mutational Analysis; D020224:Expressed Sequence Tags; D005347:Fibroblasts; D005656:Fungal Proteins; D015723:Gene Library; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008830:Microbodies / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015211:Zellweger Syndrome / Q000235:genetics* / Q000378:metabolism
D005656:Fungal Proteins; D008565:Membrane Proteins; C486345:PEX16 protein, human; D011993:Recombinant Fusion Proteins