Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor
Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor
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DOI：
10.1038/ng0497-377
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发表时间：
1997-04-01
期刊：
影响因子：
30.8
通讯作者：
Distel, B
中科院分区：
文献类型：
--
作者：
Motley, AM;Hettema, EH;Distel, B
根肿性点状软骨发育不良(RCDP)是一种常染色体隐性遗传病，临床特征是身材矮小，主要累及四肢近端，典型的面部畸形，先天性肌挛缩和严重的生长发育和智力低下。虽然有些患者有单酶缺乏，但大多数RCDP患者(86%)属于单一互补组(CG11，也称为互补组I，阿姆斯特丹命名法[1])。来自CG11的细胞表现出四种生化异常：i)二羟基丙酮磷酸酰基转移酶，ii)烷基二羟基丙酮磷酸合成酶，iii)植酸α-氧化和iv)不能输入过氧化物体硫解酶。这些缺陷表明参与了正确靶向这些过氧化体蛋白所需的成分。在酿酒酵母pex5和PEX7突变体(2-6)中也发现了过氧化体靶向的缺陷，这两个突变体显示出与两个过氧体靶向序列(PTS1和PTS2)相对应的差异蛋白质导入缺陷。这些突变体分别缺乏它们的PTS1和PTS2受体。像酿酒酵母PEX7细胞一样，来自CG11的RCDP细胞不能导入ptsZ报告蛋白(7)。在这里，我们报道了编码人PTZ受体的PEX7的克隆，基于它与两个酵母同源物的相似性。所有来自CG11的可检测到PEX7 mRNA的RCDP患者都被发现含有PEX7突变。导致PEX7 C端截断的突变与疾病相关，并且在CG11的RCDP成纤维细胞中表达PEX7可以挽救ptsZ蛋白导入缺陷。这些发现证明PEX7的突变导致RCDP，CG11。
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disease characterized clinically by a disproportionately short stature primarily affecting the proximal parts of the extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Although some patients have single enzyme deficiencies, the majority of RCDP patients (86%) belong to a single complementation group (CG11, also known as complementation group I, Amsterdam nomenclature(1)). Cells from CG11 show a tetrad of biochemical abnormalities: a deficiency of i) dihydroxyacetonephosphate acyltransferase, ii) alkyldihydroxyacetonephosphate synthase, iii) phytanic acid alpha-oxidation and iv) inability to import peroxisomal thiolase. These deficiencies indicate involvement of a component required for correct targeting of these peroxisomal proteins. Deficiencies in peroxisomal targeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutants(2-6), which show differential protein import deficiencies corresponding to two peroxisomal targeting sequences (PTS1 and PTS2). These mutants lack their PTS1 and PTS2 receptors, respectively. Like S. cerevisiae pex7 cells, RCDP cells from CG11 cannot import a PTSZ reporter protein(7). Here we report the cloning of PEX7 encoding the human PTSZ receptor, based on its similarity to two yeast orthologues. All RCDP patients from CG11 with detectable PEX7 mRNA were found to contain mutations in PEX7. A mutation resulting in C-terminal truncation of PEX7 cosegregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTSZ protein import deficiency. These findings prove that mutations in PEX7 cause RCDP, CG11.