A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency.
A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency.
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DOI：
10.7554/elife.57831
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发表时间：
2020-12-14
期刊：
影响因子：
7.7
通讯作者：
Chow CY
中科院分区：
文献类型：
--
作者：
Talsness DM;Owings KG;Coelho E;Mercenne G;Pleinis JM;Partha R;Hope KA;Zuberi AR;Clark NL;Lutz CM;Rodan AR;Chow CY
N-聚糖酶 1 (NGLY1) 是一种细胞质去糖基化酶。 NGLY1 基因的功能丧失突变会导致 NGLY1 缺陷，其特点是发育迟缓、癫痫发作以及缺乏汗水和眼泪。为了模拟患者中观察到的表型变异性，我们将 NGLY1 缺陷的果蝇模型与一组遗传多样性菌株进行杂交。所得后代显示出 0 至 100% 致死率的表型谱。对致死表型的关联分析以及进化率协变分析生成了修饰基因列表，从而提供了对 NGLY1 功能和疾病的深入了解。排名最高的关联命中是 Ncc69（人 NKCC1/2），一种保守的离子转运蛋白。对 NGLY1-/- 小鼠细胞的分析表明，NKCC1 的平均分子量发生了改变，功能也降低了。这种离子转运蛋白的失调可能解释了在 NGLY1 缺陷患者中观察到的分泌性上皮功能缺陷。
N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0 to 100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1-/- mouse cells demonstrated that NKCC1 has an altered average molecular weight and reduced function. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.