Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and developmental defects. Genome-wide linkage analysis localized the critical interval to chromosome 12p with a maximum two-point LOD score of 4.2 (θ = 0). Next-generation exome sequencing identified a novel homozygous missense variant (c.653 T > C; p.F218S) in peroxisomal biogenesis factor 5 (PEX5), a peroxisome import receptor protein. This missense mutation was confirmed by bidirectional Sanger sequencing. It segregated with the disease phenotype in the family and was absent in ethnically matched control chromosomes. The lens-specific knockout mice of Pex5 recapitulated the cataractous phenotype. In vitro import assays revealed a normal capacity of the mutant PEX5 to enter the peroxisomal Docking/Translocation Module (DTM) in the presence of peroxisome targeting signal 1 (PTS1) cargo protein, be monoubiquitinated and exported back into the cytosol. Importantly, the mutant PEX5 protein was unable to form a stable trimeric complex with peroxisomal biogenesis factor 7 (PEX7) and a peroxisome targeting signal 2 (PTS2) cargo protein and, therefore, failed to promote the import of PTS2 cargo proteins into peroxisomes. In conclusion, we report a novel missense mutation in PEX5 responsible for the defective import of PTS2 cargo proteins into peroxisomes resulting in congenital cataracts and developmental defects.

过氧化物酶体，单膜细胞内细胞器，在各种代谢途径中起重要作用。蛋白质从胞质溶胶到过氧化物酶体的转运取决于过氧化物酶体导入受体蛋白，过氧化物酶体运输的缺陷导致广泛的过氧化物酶体疾病。在这里，我们报道一个常染色体隐性先天性白内障和发育缺陷的近亲大家庭。全基因组连锁分析将关键区间定位在12p染色体上，最大两点LOD得分为4.2（θ  = 0）。下一代外显子测序鉴定了新的纯合错义变异体（c.653 T> C。; p.F218S）在过氧化物酶体生物合成因子5（PEX5），过氧化物酶体导入受体蛋白。通过双向Sanger测序证实了这种错义突变。它与家族中的疾病表型隔离，在种族匹配的对照染色体中不存在。Pex5的晶状体剔除小鼠概括了白内障的表型。体外导入试验显示，在存在过氧化物酶体靶向信号1（PTS1）货物蛋白的情况下，突变体PEX5进入过氧化物酶体对接/转运模块（DTM）的正常能力，被单泛素化并输出回到细胞质中。重要的是，突变的PEX5蛋白无法与过氧化物酶体生物发生因子7（PEX7）和过氧化物酶体靶向信号2（PTS2）货物蛋白形成稳定的三聚体复合物，因此无法促进PTS2货物蛋白向过氧化物酶体的导入。总之，我们报告了PEX5中的一种新型错义突变，导致PTS2货物蛋白向过氧化物酶体的缺陷导入，导致先天性白内障和发育缺陷。