Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene
Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene
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DOI：
10.1038/ng1097-190
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发表时间：
1997-10-01
期刊：
影响因子：
30.8
通讯作者：
Wanders, RJA
中科院分区：
文献类型：
--
作者：
Jansen, GA;Ferdinandusse, S;Wanders, RJA
Refsum病是一种常染色体隐性遗传疾病，其临床特征为四种异常：视网膜色素变性、周围神经病变、小脑性共济失调和脑脊液（CSF）蛋白水平升高，但脑脊液中细胞数量不增加。所有患者都表现出一种不寻常的支链脂肪酸——植酸（3,7,11,15-四甲基六酸）在血液和组织中的积累。从生化角度看，这种疾病是由于缺乏植烷酰辅酶a羟化酶（PhyH）引起的，PhyH是一种催化植烷酸α -氧化第一步的过氧化物酶体蛋白。我们从大鼠肝脏过氧化物酶体中纯化了PhyH，并确定了n端氨基酸序列，以及lysc消化纯化蛋白后获得的额外内部氨基酸序列。利用这些部分氨基酸序列对EST数据库进行检索，鉴定出编码PhyH的全长人cDNA序列：该开放阅读框编码41.2 kd蛋白，包含338个氨基酸，包含可切割过氧化物酶体靶向信号类型2 （PTS2）。对5例Refsum病患者的PHYH成纤维细胞cDNA进行序列分析，发现不同的突变，包括1个核苷酸缺失，111个核苷酸缺失和一个点突变。这一分析证实了我们的发现，即Refsum病是由PhyH缺乏引起的。
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.