Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease.
Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease.
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DOI：
10.1242/bio.20147559
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发表时间：
2014-04-04
期刊：
影响因子：
2.4
通讯作者：
Grotewiel M
中科院分区：
文献类型：
--
作者：
Jones MA;Amr S;Ferebee A;Huynh P;Rosenfeld JA;Miles MF;Davies AG;Korey CA;Warrick JM;Shiang R;Elsea SH;Girirajan S;Grotewiel M
Wolfram综合征（WFS）是一种进行性神经退行性疾病，其特征是尿崩症、糖尿病、视神经萎缩和耳聋。WFS 1和WFS 2分别由Wolfram综合征1（WFS 1）和CDGSH铁硫结构域2（CISD 2）基因的隐性突变引起。为了探索CISD 2的功能，我们在果蝇直系同源物CISD 2表达改变的果蝇中进行了遗传研究。令人惊讶的是，具有强烈的普遍存在的RNAi介导的cisd 2敲低的果蝇没有明显的寿命改变、应激抗性、运动行为或其他几种表型的迹象。然而，我们随后发现，在有针对性的遗传筛选中，cisd 2功能的改变了过表达两种溶酶体贮积病基因的果蝇直向同源物的影响，棕榈酰蛋白硫酯酶1（人类的PPT 1，果蝇的Ppt 1）和蜡样脂褐质沉积症，神经元3（人类的CLN 3，果蝇的cln 3），对果蝇的眼睛形态。我们还发现，cln 3修改过表达Ppt 1的影响，在眼睛和过表达的cln 3相互作用的cisd 2的功能突变的损失，破坏果蝇的运动能力。后续的多物种生物信息学分析表明，以CISD 2、PPT 1和CLN 3为中心的基因网络可能通过改变碳水化合物代谢、蛋白质折叠和内肽酶活性来影响疾病。人类遗传学研究表明，包括CLN 3在内的拷贝数变异（重复和缺失），以及CISD 2/PPT 1/CLN 3网络中可能的另一个基因，在发育迟缓的个体中过度表达。我们的研究表明，cisd 2，Ppt 1和cln 3在苍蝇中协同发挥作用，这表明CISD 2，PPT 1和CLN 3在人类中也可能协同发挥作用。此外，我们的研究提出了这样的可能性，即WFS 2和一些溶酶体贮积症可能受到共同机制的影响，并且潜在的基因可能对发育迟缓具有以前未被认识到的影响。
Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
10.5
作者：
Chen, Yi-Fan;Kao, Cheng-Heng;Tsai, Ting-Fen
通讯作者：
Tsai, Ting-Fen
影响因子：
8.8
作者：
Bachmann-Gagescu, Ruxandra;Mefford, Heather C.;Tsuchiya, Karen D.
通讯作者：
Tsuchiya, Karen D.
影响因子：
64.5
作者：
Freeman, M
通讯作者：
Freeman, M
影响因子：
3.3
作者：
Fergestad, Tim;Bostwick, Bret;Ganetzky, Barry
通讯作者：
Ganetzky, Barry