Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B

Hum Mol Genet. 1998 Sep;7(9):1399-405. doi: 10.1093/hmg/7.9.1399.

Abstract

Peroxisome biogenesis disorders (PBD), such as Zellweger syndrome, are autosomal recessive diseases caused by a deficiency in peroxisome assembly as well as a malfunction of the peroxisomes, where at least 10 genotypes have been reported. We have isolated a human PEX10 cDNA (HsPEX10) by an expressed sequence tag homology search on a human DNA database using yeast PEX10 from Hansenula polymorpha, followed by screening of a human liver cDNA library. This cDNA encodes a peroxisomal protein (a peroxin Pex10p) comprising 326 amino acids, with two putative transmembrane segments and a C3HC4zinc finger RING motif. Both the N- and C-terminal regions of Pex10p are exposed to the cytosol, as assessed by an expression study of epitope-tagged Pex10p. HsPEX10 expression morphologically and biochemically restored peroxisome biogenesis in fibroblasts from Zellweger patients of complementation group B in Japan (complementation group VII in the USA). One patient (PBDB-01) possessed a homozygous, inactivating mutation, a 2 bp deletion immediately upstream of the RING motif, which resulted in a frameshift, altering 65 amino acids from the normal. This implies that the C-terminal part, including the RING finger, is required for biological function of Pex10p. PEX10 cDNA derived from patient PBDB-01 was defective in peroxisome-restoring activity when expressed in patient fibroblasts. These results demonstrate that mutation in PEX10 is the genetic cause of complementation group B PBD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • DNA, Complementary / genetics
  • DNA, Complementary / isolation & purification
  • Fungal Proteins / genetics
  • Gene Expression
  • Genetic Complementation Test
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Oligonucleotide Probes / genetics
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • Pichia / genetics
  • Proteins / genetics*
  • Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Transfection
  • Zellweger Syndrome / genetics*

Substances

  • DNA, Complementary
  • Fungal Proteins
  • Oligonucleotide Probes
  • Proteins
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • PHEX protein, human