Identification of PAHX, a Refsum disease gene

Nat Genet. 1997 Oct;17(2):185-9. doi: 10.1038/ng1097-185.


Refsum disease is an autosomal recessive disorder characterized by retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia and increased cerebrospinal fluid protein. Biochemically, the disorder is defined by two related properties: pronounced accumulation of phytanic acid and selective loss of the peroxisomal dioxygenase required for alpha-hydroxylation of phytanoyl-CoA2. Decreased phytanic-acid oxidation is also observed in human cells lacking PEX7, the receptor for the type-2 peroxisomal targetting signal (PTS2; refs 3,4), suggesting that the enzyme defective in Refsum disease is targetted to peroxisomes by a PTS2. We initially identified the human PAHX and mouse Pahx genes as expressed sequence tags (ESTs) capable of encoding PTS2 proteins. Human PAHX is targetted to peroxisomes, requires the PTS2 receptor for peroxisomal localization, interacts with the PTS2 receptor in the yeast two-hybrid assay and has intrinsic phytanoyl-CoA alpha-hydroxylase activity that requires the dioxygenase cofactor iron and cosubstrate 2-oxoglutarate. Radiation hybrid data place PAHX on chromosome 10 between the markers D10S249 and D10S466, a region previously implicated in Refsum disease by homozygosity mapping. We find that both Refsum disease patients examined are homozygous for inactivating mutations in PAHX, demonstrating that mutations in PAHX can cause Refsum disease.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromosome Mapping
  • Chromosomes, Human, Pair 10 / genetics
  • DNA Mutational Analysis
  • DNA Primers / genetics
  • DNA, Complementary / genetics
  • Gene Expression
  • Homozygote
  • Humans
  • Mice
  • Microbodies / metabolism
  • Mixed Function Oxygenases / genetics*
  • Mixed Function Oxygenases / metabolism
  • Molecular Sequence Data
  • Peroxisomal Targeting Signal 2 Receptor
  • Polymerase Chain Reaction
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Refsum Disease / genetics*
  • Refsum Disease / metabolism
  • Sequence Homology, Amino Acid
  • Species Specificity


  • DNA Primers
  • DNA, Complementary
  • PEX7 protein, human
  • Peroxisomal Targeting Signal 2 Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Mixed Function Oxygenases
  • PHYH protein, human
  • Phyh protein, mouse

Associated data

  • GENBANK/AF023462
  • GENBANK/AF023463