Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications
Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications
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DOI：
10.1007/s00439-002-0761-z
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发表时间：
2002-08-01
期刊：
影响因子：
5.3
通讯作者：
Nakahata, T
中科院分区：
文献类型：
--
作者：
Yorifuji, T;Kawai, M;Nakahata, T
丙酸血症 [MIM 606054] 是一种由丙酰辅酶 A 羧化酶 (PCC) 遗传缺陷引起的有机酸血症，其特征是在新生儿期或婴儿早期开始出现严重的代谢性酸血症和高氨血症。然而，有些患者的 PCC 活动较高，但随后出现异常症状，如轻度智力低下或锥体外系症状，有时甚至没有代谢性酸中毒。通过对超过 130,000 名日本新生儿进行新生儿筛查，我们发现丙酸血症患者的发生频率比之前报道的高十倍以上，其中大多数患者表型较轻。突变谱与重症患者有很大不同，PCC 基因（PCCB）β 亚基存在常见突变（Y435C）。由于轻度患者可能会出现不寻常的症状，因此很容易被忽视，因此识别这些患者并澄清他们的自然病史非常重要。从分子角度来看，其中一个突变 (A1288C) 导致了不寻常的多外显子跳跃模式，而另一个未识别的突变则导致 mRNA 缺失。考虑到先前有关 PCCB 突变的发现，该基因似乎特别容易发生转录后修饰，例如错义介导的外显子跳跃、mRNA 衰减或快速产物降解。
Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the beta subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to post-transcriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.