Lee M H, Hazard S, Carpten J D, Yi S, Cohen J, Gerhardt G T, Salen G, Patel S B
Division of Endocrinology, Medical University of South Carolina, Charleston 29403, USA.
J Lipid Res. 2001 Feb;42(2):159-69.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.
脑腱黄瘤病（CTX）是一种罕见的常染色体隐性胆汁酸生物合成障碍疾病。临床上，CTX患者表现为腱黄瘤、青少年白内障和进行性神经功能障碍，可通过检测血浆胆甾烷醇水平升高来诊断。CTX是由影响甾醇27-羟化酶基因（CYP27）的突变引起的。CTX已在多个群体中被识别，但在日本、西班牙裔犹太人和意大利人群中似乎具有更高的患病率。我们收集了来自美国的12个先前未报道的家系。CYP27基因座先前已被定位到染色体2q33-qter。我们进行了连锁分析，未发现遗传异质性的证据。所有CTX患者均显示与CYP27基因座连锁，单倍型分析和重组事件使我们能够将CYP27精确地定位到染色体2q35，位于标记D2S137和D2S424之间。到目前为止，从13名先证者中鉴定出23个突变；11个为复合杂合子，2个为纯合突变。其中，5个是新突变[Trp100Stop、Pro408Ser、Gln428Stop、CYP27基因外显子1中的10个碱基对（bp）缺失和外显子6中的2-bp缺失]。甾醇27-羟化酶的三维结构模型显示，虽然大多数错义突变破坏了对酶活性至关重要的血红素结合域和肾上腺皮质铁氧化还原蛋白结合域，但两个错义突变（Arg94Trp/Gln和Lys226Arg）明显位于这些位点之外，可能确定了一个潜在的底物结合位点或其他蛋白质接触位点。
