Molecular basis for peroxisome biogenesis disorders
Molecular basis for peroxisome biogenesis disorders
复制标题
过氧化物酶体生物发生障碍的分子基础
DOI：
10.1007/978-3-7091-1788-0_5
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
S.
中科院分区：
文献类型：
--
作者：
*Fujiki;Y.;Okumoto;K.;Mukai;S.;and Tamura;S.
过氧化物酶体在人类中的功能重要性通过过氧化物酶体缺陷型过氧化物酶体生物发生障碍（PBD）（例如Zellweger综合征（ZS））、常染色体隐性和进行性障碍而突出，所述进行性障碍的特征在于多种过氧化物酶体代谢功能的丧失和过氧化物酶体组装缺陷，其由13个互补基团（CG）组成。采用两种不同但互补的方法，一种是利用十几个过氧化物酶体缺陷型中国仓鼠卵巢（CHO）细胞突变体的CG进行正向遗传学研究，另一种是利用酵母过氧化物酶（PEX）基因筛选人类表达序列标签（EST）数据库进行同源性搜索，以分离出酵母PEX基因。现在完成了对所有13个CG的PBD负责的致病基因的搜索。鉴定了膜组装和基质蛋白输入所需的过氧化物酶基因缺陷：10个哺乳动物致病性过氧化物酶Pex 1 p、Pex 2 p、Pex 5 p、Pex 6p、Pex 7 p、Pex 10 p、Pex 12 p、Pex 13 p、Pex 14 p和Pex 26 p，它们是PBD的10个CG输入基质蛋白所需的; Pex 3 p、Pex 16 p和Pex 19 p是过氧化物酶体膜组装所必需的，分别是12、9和14三个CG的PBD中最严重的ZS的原因; PEX 11 β突变导致CG 16细胞中过氧化物酶体的异常形态发生具有PEX 3、PEX 16和PEX 19缺陷的严重ZS患者倾向于携带严重的突变，如无义突变、移码和缺失。使用PEX基因进行产前DNA诊断现在可以用于所有13个CG的PBD。
The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome (ZS), autosomal recessive, and progressive disorders characterized by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of 13 complementation groups (CGs). Two mutually distinct but complementary approaches, forward genetic approach using more than a dozen CGs of peroxisome-deficient Chinese hamster ovary (CHO) cell mutants and the homology search by screening the human expressed sequence tag (EST) database using yeast peroxin (PEX) genes, have been taken in order to isolate mammalianPEXgenes. Search for pathogenic genes responsible for PBDs of all 13 CGs is now accomplished. Gene defects of peroxins required for both membrane assembly and matrix protein import are identified: ten mammalian pathogenic peroxins, Pex1p, Pex2p, Pex5p, Pex6p, Pex7p, Pex10p, Pex12p, Pex13p, Pex14p, and Pex26p, for 10 CGs of PBDs, are required for matrix protein import; three, Pex3p, Pex16p, and Pex19p, are essential for peroxisome membrane assembly and responsible for the most severe ZS in PBDs of three CGs, 12, 9, and 14, respectively;PEX11βmutation causes dysmorphogenesis of peroxisomes in ZS-like phenotype of CG16. Patients with severe ZS with defects ofPEX3,PEX16, andPEX19tend to carry severe mutation such as nonsense mutations, frameshifts, and deletions. Prenatal DNA diagnosis usingPEXgenes is now possible for PBDs of all 13 CGs.