Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene

被引:217
作者
Jansen, GA
Ferdinandusse, S
Ijlst, L
Muijsers, AO
Skjeldal, OH
Stokke, O
Jakobs, C
Besley, GTN
Wraith, JE
Wanders, RJA
机构
[1] UNIV AMSTERDAM,ACAD MED CTR,DEPT CLIN BIOCHEM,NL-1100 DE AMSTERDAM,NETHERLANDS
[2] UNIV AMSTERDAM,ACAD MED CTR,DEPT PEDIAT,NL-1100 DE AMSTERDAM,NETHERLANDS
[3] UNIV AMSTERDAM,EC SLATER INST,NL-1018 TV AMSTERDAM,NETHERLANDS
[4] UNIV OSLO,RIKSHOSP,INST CLIN BIOCHEM,DEPT PEDIAT,N-0027 OSLO 1,NORWAY
[5] FREE UNIV AMSTERDAM HOSP,DEPT CLIN CHEM,METAB UNIT,NL-1081 HV AMSTERDAM,NETHERLANDS
[6] ROYAL MANCHESTER CHILDRENS HOSP,WILLINK BIOCHEM GENET UNIT,MANCHESTER M27 4HA,LANCS,ENGLAND
关键词
D O I
10.1038/ng1097-190
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页码:190 / 193
页数:4
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