Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder
Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder
复制标题
DOI：
10.1038/sj.ejhg.5201090
复制
发表时间：
2004-02-01
影响因子：
5.2
通讯作者：
Wanders, RJA
中科院分区：
文献类型：
--
作者：
Gootjes, J;Schmohl, F;Wanders, RJA
过氧化物酶体生物发生障碍（PBDs）由于至少11种不同基因的缺陷而形成了一组遗传和临床异质性的疾病。这组疾病的原型是齐薇格综合征（ZS），新生儿肾上腺白质营养不良（NALD）和婴儿Refsum病（IRD）是较轻的变体。肝病、可变神经发育迟缓、视网膜病变和感知性耳聋是PBDs的常见症状。属于互补组3 （CG3）的PBD患者有PEX12基因突变，该基因编码一种蛋白质（PEX12），该蛋白质包含两个跨膜结构域，以及一个锌结合结构域，该结构域对于与过氧化物酶体蛋白质进口机制中的其他蛋白质相互作用很重要。我们报告了5例属于CG3的PBD患者的鉴定。对他们的PEX12基因的序列分析揭示了五种不同的突变，其中四种以前没有报道过。其中4例患者的突变破坏了翻译框和/或在PEX12开放阅读框中产生了一个早期终止密码子，预计会导致蛋白产物截断，至少缺乏cooh末端锌结合域。这些患者均表现出较严重的表型（ZS或NALD）。第五名患者表达两个PEX12等位基因，能够编码一种含有锌结合结构域的蛋白质，并表现出较温和的表型（IRD）。在成纤维细胞中测定的三种生化标志物（DHAPAT活性、C26:0 β -氧化和β -氧化）也与基因型相关。因此，我们的CG3患者的基因型与患者的生化和临床表型具有良好的相关性。
The peroxisome biogenesis disorders (PBDs) form a genetically and clinically heterogeneous group of disorders due to defects in at least 11 distinct genes. The prototype of this group of disorders is Zellweger syndrome (ZS), with neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) as milder variants. Liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness are common to PBDs. PBD patients belonging to complementation group 3 (CG3) have mutations in the PEX12 gene, which codes for a protein ( PEX12) that contains two transmembrane domains, and a zinc-binding domain considered to be important for its interaction with other proteins of the peroxisomal protein import machinery. We report on the identification of five PBD patients belonging to CG3. Sequence analysis of their PEX12 genes revealed five different mutations, four of which have not been reported before. Four of the patients have mutations that disrupt the translation frame and/or create an early termination codon in the PEX12 open reading frame predicted to result in truncated protein products, lacking at least the COOH-terminal zinc-binding domain. All these patients display the more severe phenotypes ( ZS or NALD). The fifth patient expresses two PEX12 alleles capable of encoding a protein that does contain the zinc-binding domain and displayed a milder phenotype ( IRD). The three biochemical markers measured in fibroblasts (DHAPAT activity, C26:0 beta-oxidation and pristanic acid beta-oxidation) also correlated with the genotypes. Thus, the genotypes of our CG3 patients show a good correlation with the biochemical and clinical phenotype of the patients.