Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases.
Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases.
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DOI：
10.1242/jcs.258568
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发表时间：
2021-07-15
影响因子：
4
通讯作者：
Drummond IA
中科院分区：
文献类型：
--
作者：
Cardenas-Rodriguez M;Austin-Tse C;Bergboer JGM;Molinari E;Sugano Y;Bachmann-Gagescu R;Sayer JA;Drummond IA
CEP290（也称为NPHP6）是一种大的多结构域卷曲卷曲蛋白，其突变与多种纤毛相关综合征有关。超过130个CEP290突变与广泛的人类纤毛病有关，这就提出了单个基因突变如何引起不同疾病综合征的问题。在斑马鱼中，cep290缺陷的表达性与基因消融的类型有关：急性cep290 morpholino敲低导致严重的纤毛相关表型，而CRISPR/Cas9基因突变的缺陷仅限于光感受器缺陷。在这里，我们发现基因突变中的温和表型与编码纤毛相关的小gtpase arl3， arl13b和unc119b的基因上调有关。在人Joubert综合征CEP290患者的尿源性肾上皮细胞中也观察到UNC119b的上调。在cep290突变斑马鱼胚胎中，arl3、arl13b和unc119b的异位表达挽救了Kupffer囊泡纤毛，部分挽救了光感受器外段缺陷。结果表明，通过上调参与常见亚细胞过程（脂化蛋白转运到纤毛）的基因进行遗传补偿，可能是导致CEP290缺陷中基因型-表型变化的保守机制。摘要：纤毛病基因突变的影响取决于细胞类型，并且可以通过在相同纤毛膜蛋白传递途径中起作用的其他基因的表达来补偿。
Mutations in CEP290 (also known as NPHP6), a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish, the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes, whereas deficiencies in a CRISPR/Cas9 genetic mutant were restricted to photoreceptor defects. Here, we show that milder phenotypes in genetic mutants were associated with the upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human Joubert syndrome CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies. Summary: The impact of a ciliopathy gene mutation depends on cell type, and can be compensated for by expression of other genes that function in the same cilia membrane protein delivery pathway.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
9.8
作者：
Gorden, Nicholas T.;Arts, Heleen H.;Doherty, Dan
通讯作者：
Doherty, Dan
影响因子：
3.5
作者：
Baye LM;Patrinostro X;Swaminathan S;Beck JS;Zhang Y;Stone EM;Sheffield VC;Slusarski DC
通讯作者：
Slusarski DC
影响因子：
4.5
作者：
Anderson JL;Mulligan TS;Shen MC;Wang H;Scahill CM;Tan FJ;Du SJ;Busch-Nentwich EM;Farber SA
通讯作者：
Farber SA
DOI：
10.1083/jcb.201006105
发表时间：
2010-09-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Craige B;Tsao CC;Diener DR;Hou Y;Lechtreck KF;Rosenbaum JL;Witman GB
通讯作者：
Witman GB