title: Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.
abstract: Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF. All patients exhibit accumulation of an unusual branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), in blood and tissues. Biochemically, the disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid. We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein. A search of the EST database with these partial amino-acid sequences led to the identification of the full-length human cDNA sequence encoding PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which contains a cleavable peroxisomal targeting signal type 2 (PTS2). Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation. This analysis confirms our finding that Refsum disease is caused by a deficiency of PhyH.
authors.affiliation: Department of Clinical Biochemistry, University of Amsterdam, The Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Jansen
authors.forename: R
authors.initials: R
authors.lastname: Ofman
authors.forename: S
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: L
authors.initials: L
authors.lastname: Ijlst
authors.forename: A O
authors.initials: AO
authors.lastname: Muijsers
authors.forename: O H
authors.initials: OH
authors.lastname: Skjeldal
authors.forename: O
authors.initials: O
authors.lastname: Stokke
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
authors.forename: G T
authors.initials: GT
authors.lastname: Besley
authors.forename: J E
authors.initials: JE
authors.lastname: Wraith
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D008099:Liver / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000302:isolation & purification; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D051381:Rats; D012035:Refsum Disease / Q000201:enzymology* / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D006899:Mixed Function Oxygenases; C102623:PHYH protein, human; C491171:Phyh protein, rat