Walter C, Gootjes J, Mooijer P A, Portsteffen H, Klein C, Waterham H R, Barth P G, Epplen J T, Kunau W H, Wanders R J, Dodt G
Institut für Physiologische Chemie, Abteilung für Zellbiochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum, Germany.
Am J Hum Genet. 2001 Jul;69(1):35-48. doi: 10.1086/321265. Epub 2001 Jun 1.
Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are clinically overlapping syndromes, collectively called "peroxisome biogenesis disorders" (PBDs), with clinical features being most severe in ZS and least pronounced in IRD. Inheritance of these disorders is autosomal recessive. The peroxisome biogenesis disorders are genetically heterogeneous, having at least 12 different complementation groups (CGs). The gene affected in CG1 is PEX1. Approximately 65% of the patients with PBD harbor mutations in PEX1. In the present study, we used SSCP analysis to evaluate a series of patients belonging to CG1 for mutations in PEX1 and studied phenotype-genotype correlations. A complete lack of PEX1 protein was found to be associated with severe ZS; however, residual amounts of PEX1 protein were found in patients with the milder phenotypes, NALD and IRD. The majority of these latter patients carried at least one copy of the common G843D allele. When patient fibroblasts harboring this allele were grown at 30 degrees C, a two- to threefold increase in PEX1 protein levels was observed, associated with a recovery of peroxisomal function. This suggests that the G843D missense mutation results in a misfolded protein, which is more stable at lower temperatures. We conclude that the search for the factors and/or mechanisms that determine the stability of mutant PEX1 protein by high-throughput procedures will be a first step in the development of therapeutic strategies for patients with mild PBDs.
泽韦格综合征（ZS）、新生儿肾上腺脑白质营养不良（NALD）和婴儿型雷夫叙姆病（IRD）是临床上有重叠表现的综合征，统称为“过氧化物酶体生物发生障碍”（PBDs），其中ZS的临床特征最为严重，IRD最不明显。这些疾病的遗传方式为常染色体隐性遗传。过氧化物酶体生物发生障碍在遗传上具有异质性，至少有12个不同的互补群（CGs）。CG1中受影响的基因是PEX1。大约65%的PBD患者在PEX1基因中存在突变。在本研究中，我们使用单链构象多态性分析（SSCP）来评估一系列属于CG1的患者的PEX1基因突变情况，并研究表型-基因型的相关性。结果发现，完全缺乏PEX1蛋白与严重的ZS相关；然而，在表型较轻的NALD和IRD患者中发现了残余量的PEX1蛋白。这些病情较轻的患者大多数携带至少一个常见的G843D等位基因拷贝。当携带该等位基因的患者成纤维细胞在30摄氏度下培养时，观察到PEX1蛋白水平增加了两到三倍，同时过氧化物酶体功能也得到了恢复。这表明G843D错义突变导致了一种错误折叠的蛋白，该蛋白在较低温度下更稳定。我们得出结论，通过高通量方法寻找决定突变型PEX1蛋白稳定性的因素和/或机制，将是为轻度PBD患者制定治疗策略的第一步。
