Mutation in PEX16 Is Causal in the Peroxisome-Deficient Zellweger Syndrome of Complementation Group D

Am J Hum Genet. 1998 Dec;63(6):1622-30. doi: 10.1086/302161.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • DNA Mutational Analysis
  • Expressed Sequence Tags
  • Fibroblasts
  • Fungal Proteins*
  • Gene Library
  • Genetic Complementation Test
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Liver
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Microbodies / metabolism*
  • Molecular Sequence Data
  • Mutation*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Nucleic Acid
  • Zellweger Syndrome / genetics*
  • Zellweger Syndrome / metabolism

Substances

  • Fungal Proteins
  • Membrane Proteins
  • PEX16 protein, human
  • Recombinant Fusion Proteins

Associated data

  • GENBANK/AB016531