Imprinting at the SMPD1 locus:: Implications for acid sphingomyelinase-deficient Niemann-Pick disease
Imprinting at the SMPD1 locus:: Implications for acid sphingomyelinase-deficient Niemann-Pick disease
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DOI：
10.1086/503750
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发表时间：
2006-05-01
影响因子：
9.8
通讯作者：
Schuchman, EH
中科院分区：
文献类型：
--
作者：
Simonaro, CM;Park, JH;Schuchman, EH
酸性鞘磷脂酶 (ASM) 是 A 型和 B 型尼曼-匹克病 (NPD) 中缺乏的脂质水解酶。在这里，我们证明编码 ASM (SMPD1) 的基因具有父系印记，并且 ASM 缺陷 NPD 患者和携带者中突变等位基因的差异表达会影响疾病表型。对几名 NPD 患者的基因组测序与逆转录酶聚合酶链式反应测序结果进行比较，发现一种突变等位基因的优先表达。对一个家族的进一步分析表明，所表达的等位基因是母系遗传的，并且个体患者的独特临床表现与母系突变表达的残留 ASM 活性量相关。用 5-aza-2'-脱氧胞苷处理 NPD 细胞系可增强父系 SMPD1 等位基因的表达，亚硫酸氢盐基因组测序鉴定出 SMPD1 启动子内的哪些 CpG 二核苷酸被甲基化。在一组相关的研究中，我们发现了一个携带者个体，其 ASM 活性与正常 ASM 活性相似，并且具有 ASM 缺陷 NPD 的临床特征。 DNA 测序证实该个体携带单一 SMPD1 突变，并且该突变等位基因优先表达。因此，这些数据首次证明了 SMPD1 基因的印记，并揭示了这种表观遗传修饰对 ASM 缺陷 NPD 表现的影响。
Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had similar to 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD.