Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy.
Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy.
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神经酰胺合成酶TLCD3B是一个与人类隐性视网膜营养不良相关的新基因。
DOI：
10.1038/s41436-020-01003-x
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Chen R
中科院分区：
文献类型：
--
作者：
Bertrand RE;Wang J;Xiong KH;Thangavel C;Qian X;Ba-Abbad R;Liang Q;Simões RT;Sampaio SAM;Carss KJ;Lucy Raymond F;Robson AG;Webster AR;Arno G;Porto FBO;Chen R
先前的研究表明神经酰胺是一种促凋亡的脂质，因为高水平的神经酰胺可以导致神经细胞的凋亡，包括光感受器。然而，在人类患者中还没有发现神经酰胺合成酶的致病变异，小鼠的各种神经酰胺合成酶的敲除也没有导致光感受器退化。外显子组测序被用来识别标准评估方法证实的视力丧失患者的候选疾病基因，包括视网膜电描记术(ERG)和光学相干断层扫描。通过视网膜电流图和组织学分析评价小鼠视力丧失的表型。在这里，我们已经确定了来自三个携带TLCD3B致病变异的家族的四名锥视杆营养不良或黄斑病变患者。与患者观察到的表型一致，Tlcd3bKO/KO小鼠表现出视锥感光细胞光反应显著减少，外核层变薄，视网膜视锥感光细胞丢失。我们的结果提供了神经酰胺合成酶基因的功能缺失变异与人类视网膜营养不良之间的第一个联系。Tlcd3b基因敲除小鼠模型的建立将为探讨神经酰胺在光感受器细胞存活和功能中的作用提供一个独特的机会。
Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration. Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses. Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina. Our results provide the first link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, the first in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells.
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影响因子：
4.1
作者：
Mizutani, Y;Kihara, A;Igarashi, Y
通讯作者：
Igarashi, Y
CERKL 通过 NAD 依赖性脱乙酰酶 SIRT1 调节自噬
影响因子：
13.3
作者：
Hu X;Lu Z;Yu S;Reilly J;Liu F;Jia D;Qin Y;Han S;Liu X;Qu Z;Lv Y;Li J;Huang Y;Jiang T;Jia H;Wang Q;Liu J;Shu X;Tang Z;Liu M
通讯作者：
Liu M
DOI：
10.1073/pnas.1007644107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Strettoi, Enrica;Gargini, Claudia;Ghidoni, Riccardo
通讯作者：
Ghidoni, Riccardo
影响因子：
3.7
作者：
Fathinajafabadi A;Pérez-Jiménez E;Riera M;Knecht E;Gonzàlez-Duarte R
通讯作者：
Gonzàlez-Duarte R
影响因子：
4.4
作者：
German, OL;Miranda, GE;Rotstein, NP
通讯作者：
Rotstein, NP