Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.
Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.
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发表时间：
2001-02
影响因子：
6.5
通讯作者：
Mi-Hye Lee;S. Hazard;John D. Carpten;Sonia Yi;Jonathan Cohen;Glenn T. Gerhardt;Gerald Salen;Shailendra B. Patel
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文献类型：
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作者：
Mi-Hye Lee;S. Hazard;John D. Carpten;Sonia Yi;Jonathan Cohen;Glenn T. Gerhardt;Gerald Salen;Shailendra B. Patel
脑腱黄瘤病（CTX）是一种罕见的常染色体隐性遗传性胆汁酸生物合成障碍。临床上，CTX患者表现为肌腱黄色瘤、青少年白内障和进行性神经功能障碍，并且可以通过检测升高的血浆胆固醇水平来诊断。CTX由影响固醇27-羟化酶基因（CYP 27）的突变引起。已在许多人群中发现CTX，但在日本人、西班牙犹太人和意大利人群中的患病率似乎更高。我们收集了12个以前从未报道过的来自美国的家系。CYP 27基因座先前已定位于染色体2 q33-qter。我们进行了连锁分析，没有发现遗传异质性的证据。所有CTX患者均表现出与CYP 27基因座的分离，单倍型分析和重组事件使我们能够将CYP 27精确定位于染色体2 q35，标记D2 S1371和D2 S424之间。到目前为止，从分析的13个先证者中确定了23个突变; 11个是复合杂合子，2个是纯合子突变。其中，5个是新突变[Trp 100 Stop、Pro408 Ser、Gln 428 Stop、CYP 27基因外显子1中的10个碱基对（bp）缺失和外显子6中的2个碱基对缺失]。甾醇27-羟化酶的三维结构建模表明，虽然大多数的错义突变破坏血红素结合和肾上腺素结合域的酶活性的关键，两个错义突变（Arg 94 Trp/Gln和Lys 226 Arg）明确位于这些网站之外，并可能确定一个潜在的底物结合或其他蛋白质接触位点。
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.