NEJM:NAD缺乏、先天性畸形与烟酸补充

2017-08-10 xuyihan MedSci原创

先天性畸形可以表现为多种表型的组合,其发生几率比预期的要多。在许多这样的病例中,很难发现遗传原因。Hongjun Shi等研究人员寻找心脏病、脊椎和肾脏缺陷的遗传原因。

先天性畸形可以表现为多种表型的组合,其发生几率比预期的要多。在许多这样的病例中,很难发现遗传原因。Hongjun Shi等研究人员寻找心脏病、脊椎和肾脏缺陷的遗传原因。

该研究团队利用基因组测序技术鉴别患有多种先天畸形患者的家庭中潜在的致病基因突变,并通过使用体外酶活性分析和定量患者血浆中的代谢物来测试该变异体的功能。除此之外,该团队还通过CRISRP(规律成簇间隔短回文重复)-Cas9系统建立有类似变异的小鼠模型。

在两个编码犬尿氨酸途径的酶的基因上确立了变异,包括3-羟基氨基苯甲酸3,4-双加氧酶(HAAO)和犬尿氨酸酶(KYNU)。3例携带纯合子变异的患者预测HAAO或KYNU蛋白功能缺失的改变(HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21)。另一个患者携带杂合KYNU突变((p.Y156* and p.F349Kfs*4)。 突变酶的体外活性大大降低。烟酰胺腺嘌呤二核苷酸(NAD)从色氨酸通过犬尿氨酸途径从头合成。患者循环NAD水平下降。与这些患者类似的缺陷在因为NAD缺乏的Haao-敲除或Kynu-敲除的鼠胚胎中也发现了。在敲除鼠中,孕期预防NAD缺乏可避免缺陷。

由上述研究可见NAD合成中断导致人类和小鼠NAD缺乏和先天性畸形。孕期补充烟酸可防止小鼠畸形。

原始出处:

Hongjun Shi.et al. NAD Deficiency, Congenital Malformations, and Niacin Supplementation. N Engl J Med,August 10, 2017

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    2017-08-12 wushaoling
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    2017-08-12 huirong
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    2017-08-12 zblhy
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    2017-08-12 pandamao2016