Identification of novel pathogenic gene and genotype phenotype correlation in peroxisome biogenesis disorders

过氧化物酶体生物发生障碍中新致病基因和基因型表型相关性的鉴定

基本信息

批准号：
15570100
负责人：
TAMURA Shigehiko
金额：
$ 2.3万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15570100/
关键词：
peroxisome peroxisome biogenesis disorders pathogenic genes mutation analysis organelle assembly

项目摘要

The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups(CGs). CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome(ZS), to the milder neonatal adrenoleukodystrophy(NALD) and infantile Refsum disease(IRD). PEX26, encoding the 305-amino-acid membrane peroxin, has been shown to be deficient in CG8. We studied the PEX26 genotype in fibroblasts of eight CG8 patientsfour with the ZS phenotype, two with NALD, and two with IRD. Catalase was mostly cytosolic in all these cell lines, but import of the proteins that contained PTS1, the SKL peroxisome targeting sequence, was normal. Expression of PEX26 reestablished peroxisomes in all eight cell lines, confirming that PEX26 defects are pathogenic in CG8 patients. When cells were cultured at 30℃, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype. Several types of mutations were identified, including homozygous G89R mutations in two patients with ZS. Expression of these PEX26 mutations in pex26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines. These findings confirm that the degree of temperature sensitivity in pex26 cell lines is predictive of the clinical phenotype in patients with PEX26 deficiency.

人类过氧化物酶体生物发生障碍 (PBD) 分为 12 个互补组 (CG)，其中 CG8 是其中较常见的一种，与不同的表型相关，从最严重的 Zellweger 综合征 (ZS) 到较温和的表型。新生儿肾上腺脑白质营养不良（NALD）和婴儿雷夫苏姆病（IRD），编码 305 个氨基酸的膜过氧化物酶。我们研究了 8 名 CG8 患者的成纤维细胞中的 PEX26 基因型，其中四名具有 ZS 表型，两名具有 NALD，两名具有 IRD，在所有这些细胞系中，过氧化氢酶主要是胞质的，但含有 PTS1 的蛋白质。 SKL 过氧化物酶体靶向序列在所有八个细胞系中重建的 PEX26 过氧化物酶体表达均正常，证实 PEX26 缺陷在细胞系中具有致病性。当细胞在 30℃ 培养时，NALD 和 IRD 表型患者的细胞系中过氧化氢酶输入恢复，但 ZS 表型患者的恢复程度要小得多，表明温度敏感性与严重程度成反比。确定了几种类型的突变，包括两名 ZS 患者的 PEX26 突变在 pex26 中国仓鼠卵巢细胞中的表达。表型与人类细胞系相似，这些发现证实 pex26 细胞系的温度敏感性程度可以预测 PEX26 缺陷患者的临床表型。