Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders.
Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders.
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DOI：
10.1086/301963
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发表时间：
1998-08
影响因子：
9.8
通讯作者：
D. Warren;J. Morrell;H. Moser;D. Valle;Stephen J. Gould
中科院分区：
文献类型：
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作者：
D. Warren;J. Morrell;H. Moser;D. Valle;Stephen J. Gould
过氧化物酶体生物发生障碍 (PBD) 是一组遗传异质性致命疾病，其特征是神经元、肝脏和肾脏异常；严重精神障碍；最严重的情况是在出生后第一年内死亡。所有 PBD 患者的细胞均表现出一类或多类过氧化物酶体基质蛋白的输入减少，这是酵母 pex 突变体共有的表型。我们鉴定了酵母 PEX10 的人类直系同源物，并观察到其表达可挽救 PBD 患者成纤维细胞中来自互补组 7 (CG7) 的过氧化物酶体基质蛋白输入。此外，我们在两名不相关的 CG7 患者中检测到 PEX10 两个拷贝的突变。齐薇格综合征患者 PBD100 是纯合的剪接供体位点突变，导致外显子跳跃和 PEX10 开放阅读框 407 bp 丢失。一名受影响较轻的新生儿肾上腺脑白质营养不良患者是 PEX10 锌结合结构域 H290Q 错义突变和 R125ter 无义突变的复合杂合子。尽管所有三种突变都会减弱 PEX10 活性，但在轻度受影响的患者 PBD052 中检测到的两个等位基因编码部分功能的 PEX10 蛋白。 PEX10缺陷的PBD100细胞含有许多过氧化物酶体并输入过氧化物酶体膜蛋白，但不输入过氧化物酶体基质蛋白，表明PEX10的缺失对过氧化物酶体基质蛋白输入具有最显着的影响。
The peroxisome-biogenesis disorders (PBDs) are a group of genetically heterogeneous, lethal diseases that are characterized by neuronal, hepatic, and renal abnormalities; severe mental retardation; and, in their most severe form, death within the 1st year of life. Cells from all PBD patients exhibit decreased import of one or more classes of peroxisome matrix proteins, a phenotype shared by yeast pex mutants. We identified the human orthologue of yeast PEX10 and observed that its expression rescues peroxisomal matrix-protein import in PBD patients' fibroblasts from complementation group 7 (CG7). In addition, we detected mutations on both copies of PEX10 in two unrelated CG7 patients. A Zellweger syndrome patient, PBD100, was homozygous for a splice donor-site mutation that results in exon skipping and loss of 407 bp from the PEX10 open reading frame. A more mildly affected neonatal adrenoleukodystrophy patient was a compound heterozygote for a missense mutation in the PEX10 zinc-binding domain, H290Q, and for a nonsense mutation, R125ter. Although all three mutations attenuate PEX10 activity, the two alleles detected in the mildly affected patient, PBD052, encode partially functional PEX10 proteins. PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal membrane proteins but do not import peroxisomal matrix proteins, indicating that loss of PEX10 has its most pronounced effect on peroxisomal matrix-protein import.