Alamatsaz Marzieh, Jalalypour Farzaneh, Hashemi Motahare-Sadat, Shafeghati Yousef, Nasr-Esfahani Mohammad Hossein, Ghaedi Kamran
Department of Biology, Division of Cellular and Molecular Biology, Nour Danesh Institute of Higher Education, Meymeh, Isfahan, Iran.
Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
J Cell Biochem. 2021 May 6. doi: 10.1002/jcb.29945.
The peroxisome is responsible for a variety of vital pathways in primary metabolism, including the very long-chain fatty-acid oxidation and plasmalogen lipid biosynthesis. Autosomal recessive disorder of the Zellweger spectrum (ZSD) is a major subset of peroxisome biogenesis disorders (PBDs) that can be caused by mutations in any of the 14 PEX genes. Zellweger syndrome (ZS) is the foremost common and severe phenotype within the heterogeneous ZSD. However, missense mutations encode proteins with residual functions, which are associated with phenotypes that are milder than ZS. Mutations in the PEX1 gene are among the most prevalent. PEX1 and PEX6 proteins, belonging to the AAA family of ATPases, form a hexameric complex, which is associated with peroxisome membranes and essential for peroxisome biology. In this study, a two-month-old Iranian boy with hypotonia, poor feeding, and difficulty in breathing was diagnosed with Zellweger syndrome. The parents of the patient were second cousins and healthy and no similar cases were observed in the parents' family. The PEX1 gene was sequenced in the patient and his parents. The compound heterozygous mutations, p. Arg949Trp and p. Gly970Ala, were identified in the patient, while the parents were heterozygous for these alleles. Sequence analysis of the mutant PEX1 D2 domain revealed that mutation p. Arg949Trp precisely occurred in a conserved arginine residue (P4 Arg), which hinders the substrate processing of the complex. Several database records have reported mutation p. Arg949Trp(R949W) but its clinical significance is given as uncertain. We report here a novel mutation, p. Gly970Ala, which is not recorded before and may prevent proper interaction of PEX1 and PEX6 proteins. In summary, the clinical findings and peroxisome profile of the patient suggested that compound heterozygosity for these two missense mutations resulted in a nonfunctional PEX1/PEX6 complex causing the severe ZS phenotype.
过氧化物酶体负责初级代谢中的多种重要途径，包括极长链脂肪酸氧化和缩醛磷脂生物合成。常染色体隐性遗传的泽尔韦格谱系障碍（ZSD）是过氧化物酶体生物发生障碍（PBD）的一个主要亚型，可由14个PEX基因中任何一个的突变引起。泽尔韦格综合征（ZS）是异质性ZSD中最常见、最严重的表型。然而，错义突变编码具有残余功能的蛋白质，这些蛋白质与比ZS更轻的表型相关。PEX1基因的突变最为常见。属于ATP酶AAA家族的PEX1和PEX6蛋白形成一个六聚体复合物，该复合物与过氧化物酶体膜相关，对过氧化物酶体生物学至关重要。在本研究中，一名两个月大的伊朗男孩因肌张力减退、喂养困难和呼吸急促被诊断为泽尔韦格综合征。患者的父母是二级表亲且身体健康，其家族中未观察到类似病例。对患者及其父母的PEX1基因进行了测序。在患者中鉴定出复合杂合突变p.Arg949Trp和p.Gly970Ala，而其父母为这些等位基因的杂合子。对突变型PEX1 D2结构域的序列分析表明，突变p.Arg949Trp恰好发生在一个保守的精氨酸残基（P4 Arg）上，这阻碍了复合物的底物加工。多个数据库记录报道了突变p.Arg949Trp（R949W），但其临床意义尚不确定。我们在此报告一个新的突变p.Gly970Ala，此前未被记录，可能会阻止PEX1和PEX6蛋白的正常相互作用。总之，患者的临床发现和过氧化物酶体特征表明，这两个错义突变的复合杂合性导致了无功能的PEX1/PEX6复合物，从而引起严重的ZS表型。
