Human Molecular Genetics, 2000, Vol. 9, No. 8 1195-1200
© 2000 Oxford University Press
Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum’s disease
University of Amsterdam, Academic Medical Centre, Departments of 1Pediatrics (Emma Children’s Hospital) and 2Clinical Chemistry, Laboratory for Genetic Metabolic Diseases (Room F0-224), PO Box 22700, 1100 DE Amsterdam, The Netherlands, 3Free University Hospital, Department of Clinical Chemistry, Metabolic Unit, Amsterdam, The Netherlands and 4Department of Pediatrics, Institute of Clinical Biochemistry, Rikshospitalet, Oslo, Norway
Refsum’s disease (RD) is an inherited neurological syndrome biochemically characterized by the accumulation of phytanic acid in plasma and tissues. Patients with RD are unable to degrade phytanic acid due to a deficient activity of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalysing the first step of phytanic acid 
-oxidation. To enable mutation analysis of RD at the genome level, we have elucidated the genomic organization of the PHYH gene. The gene is ~21 kb and contains nine exons and eight introns. Mutation analysis of PHYH cDNA from 22 patients with RD revealed 14 different missense mutations, a 3 bp insertion, and a 1 bp deletion, which were all confirmed at the genome level. A 111 bp deletion identified in the PHYH cDNA of several patients with RD was due to either one of two different mutations in the same splice acceptor site, which result in skipping of exon 3. Six mutations, including a large in-frame deletion and five missense mutations, were expressed in the yeast Saccharomyces cerevisiae to study their effect on PhyH activity. The results showed that all these mutations lead to an enzymatically inactive PhyH protein.
+ To whom correspondence should be addressed. Tel: +31 20 5664197; Fax: +31 20 6962596; Email: wanders@amc.uva.nl
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