PEX3 is the causal gene responsible for peroxisome membrane assembly-defective Zellweger syndrome of complementation group G
PEX3 is the causal gene responsible for peroxisome membrane assembly-defective Zellweger syndrome of complementation group G
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DOI：
10.1086/303086
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发表时间：
2000-10-01
影响因子：
9.8
通讯作者：
Fujiki, Y
中科院分区：
文献类型：
--
作者：
Ghaedi, K;Honsho, M;Fujiki, Y
过氧化物酶体生物发生障碍（Peroxisome biogenesis disorders，PBD）是由过氧化物酶体组装缺陷引起的常染色体隐性遗传疾病，目前已发现13种基因型。人过氧化物酶Pex 3 p cDNA编码的373个氨基酸的过氧化物酶体膜蛋白的表达形态学和生化恢复过氧化物酶体生物合成，包括过氧化物酶体膜组装，在成纤维细胞从PBDG-02，患者与互补组G（CG-G）ZS。患者PBDG-02携带一种纯合失活突变--在342-1038位缺失97-bp核苷酸残基--导致32-氨基酸截短和诱导S-氨基酸取代和终止密码子的移码。基因组PCR分析显示，在PEX 3基因第10内含子和第11外显子交界处的剪接位点上游8个碱基处发生T → G突变，导致第11外显子全部缺失。当通过在中国仓鼠卵巢细胞的pex 3突变体和患者的成纤维细胞中的表达进行评估时，发现PBDG-02衍生的PEX 3 cDNA在过氧化物酶体恢复活性方面存在缺陷。这些结果提供了证据，PEX 3是一个新的，致病基因负责CG-G PBD。
Peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy are autosomal recessive diseases caused by defects in peroxisome assembly, for which 13 genotypes have been identified. Expression of the human peroxin Pex3p cDNA encoding a 373-amino-acid peroxisomal membrane protein morphologically and biochemically restored peroxisome biogenesis, including peroxisomal membrane assembly, in fibroblasts from PBDG-02, a patient with complementation group G (CG-G) ZS. Patient PBDG-02 carried a homozygous, inactivating mutation-a 97-bp deletion of nucleotide residues at positions 342-1038-resulting in a 32-amino-acid truncation and in a frameshift inducing both a S-amino-acid substitution and a termination codon. Genomic PCR analysis revealed mutation of T --> G at eight bases upstream of the splicing site at the boundary of intron 10 and exon 11 of PEX3 gene, giving rise to a deletion of all of exon 11. When assessed by expression in a pex3 mutant of Chinese hamster ovary cells and the patient's fibroblasts, PBDG-02-derived PEX3 cDNA was found to be defective in peroxisome-restoring activity. These results provide evidence that PEX3 is a novel, pathogenic gene responsible for CG-G PBDs.