Maternal Riboflavin Deficiency, Resulting in Transient Neonatal-Onset Glutaric Aciduria Type 2, Is Caused by a Microdeletion in the Riboflavin Transporter Gene GPR172B
Maternal Riboflavin Deficiency, Resulting in Transient Neonatal-Onset Glutaric Aciduria Type 2, Is Caused by a Microdeletion in the Riboflavin Transporter Gene GPR172B
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DOI：
10.1002/humu.21399
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发表时间：
2011-01-01
期刊：
影响因子：
3.9
通讯作者：
Christodoulou, John
中科院分区：
文献类型：
--
作者：
Ho, Gladys;Yonezawa, Atsushi;Christodoulou, John
核黄素或维生素B2是生物氧化还原反应中所需的黄素腺嘌呤二核苷酸（FAD）和黄素单核苷酸（FMN）分子的前体。我们先前曾报告一例女性新生儿，其临床和生化特征为多重酰基辅酶A脱氢酶缺乏症（MADD），经补充核黄素后得到纠正。然后发现母亲持续缺乏核黄素，这表明母亲核黄素转运的可能遗传缺陷是婴儿中观察到的短暂MADD的原因。筛选了两种最近鉴定的核黄素转运蛋白G蛋白偶联受体172 B（GPR 172 B或RFT 1）和核黄素转运蛋白2（C20 orf 54或RFT 2）的突变。在GPR 172 B中发现两个错义序列变异，c.209A>G [p.Q70R]和c.886G>A [p.V296M]。两种错义变异的体外功能研究表明，核黄素转运不受这些变异的影响。定量实时PCR显示，从头缺失GPR 172 B跨越外显子2和3中的一个等位基因从母亲。我们推测，这种核黄素转运蛋白的单倍不足导致轻度核黄素缺乏症，当再加上营养性核黄素缺乏症在怀孕期间，导致在她的新生儿中看到的一过性核黄素反应性疾病。这是第一份关于人类核黄素转运基因缺陷的报告。(C)2010 Wiley-Liss，Inc.
Riboflavin, or vitamin B2, is a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules, required in biological oxidation-reduction reactions. We previously reported a case of a newborn female who had clinical and biochemical features of multiple acyl-CoA dehydrogenation deficiency (MADD), which was corrected by riboflavin supplementation. The mother was then found to be persistently riboflavin deficient, suggesting that a possible genetic defect in riboflavin transport in the mother was the cause of the transient MADD seen in the infant. Two recently-identified riboflavin transporters G protein-coupled receptor 172B (GPR172B or RFT1) and riboflavin transporter 2 (C20orf54 or RFT2) were screened for mutations. Two missense sequence variations, c.209A>G [p.Q70R] and c.886G>A [p.V296M] were found in GPR172B. In vitro functional studies of both missense variations showed that riboflavin transport was unaffected by these variations. Quantitative real-time PCR revealed a de novo deletion in GPR172B spanning exons 2 and 3 in one allele from the mother. We postulate that haploinsufficiency of this riboflavin transporter causes mild riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, resulted in the transient riboflavin-responsive disease seen in her newborn infant. This is the first report of a genetic defect in riboflavin transport in humans. (C) 2010 Wiley-Liss, Inc.