Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.
Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.
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DOI：
10.1038/ng.2497
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发表时间：
2013-01
期刊：
影响因子：
30.8
通讯作者：
Jungbluth, Heinz
中科院分区：
文献类型：
--
作者：
Cullup, Thomas;Kho, Ay Lin;Dionisi-Vici, Carlo;Brandmeier, Birgit;Smith, Frances;Urry, Zoe;Simpson, Michael A.;Yau, Shu;Bertini, Enrico;McClelland, Verity;Al-Owain, Mohammed;Koelker, Stefan;Koerner, Christian;Hoffmann, Georg F.;Wijburg, Frits A.;ten Hoedt, Amber E.;Rogers, R. Curtis;Manchester, David;Miyata, Rie;Hayashi, Masaharu;Said, Elizabeth;Soler, Doriette;Kroisel, Peter M.;Windpassinger, Christian;Filloux, Francis M.;Al-Kaabi, Salwa;Hertecant, Jozef;Del Campo, Miguel;Buk, Stefan;Bodi, Istvan;Goebel, Hans-Hilmar;Sewry, Caroline A.;Abbs, Stephen;Mohammed, Shehla;Josifova, Dragana;Gautel, Mathias;Jungbluth, Heinz
维西综合征是一种遗传性多系统疾病，以胼胝体发育不全、白内障、心肌病、联合免疫缺陷和色素减退为特征。为了研究维西综合征的分子基础，我们对18例患者进行了外显子组和桑格序列分析。我们确定了EPG 5（以前的KIAA 1632）的隐性突变，表明在维西综合征中的致病作用。EPG 5是后生动物特异性自噬基因epg-5的人类同源物，编码与自溶体形成有关的关键自噬调节因子（异位P颗粒自噬蛋白5）。进一步的研究表明，来自EPG 5突变患者的肌肉和成纤维细胞中自噬体清除的严重阻断，导致自噬物在自噬体中积累。这些发现表明维西综合征是与缺陷性自噬相关的人类多系统疾病的范例，并表明自噬途径在器官如脑、心脏和免疫系统的解剖学和功能形成中的基本作用。
Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 patients. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homologue of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies demonstrated a severe block of autophagosomal clearance in muscle and fibroblasts from EPG5 mutant patients, resulting in autophagic cargo accumulation in autophagosomes. These findings indicate Vici syndrome as a paradigm of a human multisystem disorder associated with defective autophagy, and suggest a fundamental role of the autophagy pathway in the anatomical and functional formation of organs such as the brain, the heart and the immune system.
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DOI：
10.1083/jcb.201111053
发表时间：
2012-04-02
期刊：
The Journal of cell biology
影响因子：
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