NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes
NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes
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DOI：
10.1002/humu.10016
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发表时间：
2002-01-01
期刊：
影响因子：
3.9
通讯作者：
Rolfs, A
中科院分区：
文献类型：
--
作者：
Bauer, P;Knoblich, R;Rolfs, A
C型尼曼-匹克病（NPC）是一种罕见的常染色体隐性遗传性脂质沉积症。至少96%的NRC患者与编码溶酶体靶向蛋白的NTC 1相关。我们描述了57,052 kb的完整基因组序列，对应于人NPC 1的转录区，包括几个外显子和内含子单核苷酸多态性（SNP）。对12例无关白种人NP-C患者NPC 1的所有外显子、剪接位点和启动子区进行测序，发现9个新的和4个已知的最可能的致病突变。在两种不同突变的复合杂合子患者中观察到24种疾病等位基因中仅发现一次的10种独特突变。在总共4名患者中观察到三个错义突变中的两个，其中两个错义突变被鉴定了一次以上，这些患者对各自的突变是纯合的，沿着对潜在的单倍型也是纯合的。这些患者是最有可能的非血亲夫妇的后代。基于外显子SNPs c.2572A>G（I858 V;g.45020A>G）和c.2793C>T（N931 N; g-45686 C>T）的基因分型和分离分析，我们表征了健康高加索对照受试者的所有24个NPC 1等位基因和138个等位基因的单倍型。在对照等位基因中鉴定了两种SNP之间的所有四种排列：2572 A-2793 C（50%）、2572 G-2793 T（41%）、2572 G-2793 C（5%）和2572 A-2793 T（4%）。这些数据表明，在一个基因组片段内的祖先基因内重组，
Niemann-Pick type C disease (NPC) is a rare, autosomal recessive lipid storage disorder. At least 96% of all NRC patients link to NTC1 which encodes for a lysosomally targeted protein. We describe the complete genomic sequence of 57,052 kb corresponding to the transcribed region of human NPC1 including several exonic and intronic single nucleotide polymorphisms (SNPs). Sequencing of all exons, splice sites, and the promoter region of NPC1 in 12 unrelated Caucasian NP-C patients revealed nine novel and four known most likely disease-causing mutations. Ten unique mutations found only once in 24 disease alleles were observed in patients being compound heterozygous for two different mutations. Two of the three missense mutations identified more than once were observed in a total of four patients homozygous for the respective mutation along with homozygosity for the underlying haplotype. The patients were offspring of most likely nonconsanguineous couples. Based upon genotyping exonic SNPs c.2572A>G (I858V;g.45020A>G) and c.2793C>T (N931N; g-45686C>T) and segregation analysis we characterized the haplotype of all 24 NPC1 alleles and of 138 alleles of healthy Caucasian control subjects. All four permutations between the two SNPs were identified in the control alleles: 2572A-2793C (50%), 2572G-2793T (41%), 2572G-2793C (5%), and 2572A-2793T (4%). These data are suggestive for an ancestral intragenic recombination within a genomic fragment of