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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis
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Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

机译：单核苷酸启动子多态性改变婴儿肥厚性幽门狭窄中神经元一氧化氮合酶外显子1c的转录。

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摘要

Infantile hypertrophic pyloric stenosis (IHPS), characterized by enlarged pyloric musculature and gastric-outlet obstruction, is associated with altered expression of neuronal nitric oxide synthase (nNOS). Here we have studied molecular mechanisms by which nNOS gene expression is altered in pyloric tissues of 16 infants with IHPS and 9 controls. A significant decreased expression of total nNOS mRNA was found by quantitative RT-PCR in IHPS after normalization against GAPDH, which predominantly affected exon 1c with a reduction of 88% compared with controls (P < 0.001). After normalization against the neuronal-specific gene PGP9.5, expression of exon 1c was still decreased (P < 0.001), whereas expression of exon 1f was increased significantly (P = 0.001), indicating a compensatory up-regulation of this nNOS mRNA variant. DNA samples of 16 IHPS patients and 81 controls were analyzed for nNOS exon 1c promoter mutations and single-nucleotide polymorphism (SNP). Sequencing of the 5′-flanking region of exon 1c revealed mutations in 3 of 16 IHPS tissues, whereas 81 controls showed the wild-type sequence exclusively. Carriers of the A allele of a previously uncharacterized nNOS exon 1c promoter SNP (-84G → A) had increased risk for development of IHPS (odds ratio, 8.0; 95% confidence interval, 2.5-25.6). Reporter gene assays revealed an unchanged promoter activity for mutations but a ≈30% decrease for the -84A SNP (P < 0.001). In summary, our findings indicate that genetic alterations in the nNOS exon 1c regulatory region influence expression of the nNOS gene and may contribute to the pathogenesis of IHPS.
机译：婴儿肥大性幽门狭窄（IHPS）的特点是幽门肌肉增大和胃出口梗阻，与神经元一氧化氮合酶（nNOS）表达改变有关。在这里，我们研究了分子机制，通过这些分子机制，在16例IHPS婴儿和9例对照的幽门组织中改变nNOS基因表达。在针对GAPDH进行归一化后，通过定量RT-PCR在IHPS中发现了总nNOS mRNA的显着降低，与对照组相比，该蛋白主要影响外显子1c的降低88％（P <0.001）。在针对神经元特异性基因PGP9.5进行标准化后，外显子1c的表达仍然降低（P <0.001），而外显子1f的表达则显着增加（P = 0.001），表明该nNOS mRNA变异体的代偿性上调。分析了16位IHPS患者和81位对照的DNA样品的nNOS外显子1c启动子突变和单核苷酸多态性（SNP）。外显子1c 5'侧翼区的测序显示16个IHPS组织中有3个发生了突变，而81个对照仅显示了野生型序列。先前未表征的nNOS外显子1c启动子SNP（-84G→A）的A等位基因携带者发生IHPS的风险增加（比值比为8.0； 95％置信区间为2.5-25.6）。记者基因检测显示，突变的启动子活性未改变，但-84A SNP降低了约30％（P <0.001）。总而言之，我们的发现表明，nNOS外显子1c调控区的遗传改变影响nNOS基因的表达，并可能有助于IHPS的发病。

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