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Slc2a10 knock-out mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects.
Human Molecular Genetics ( IF 3.5 ) Pub Date : 2020-04-20 , DOI: 10.1093/hmg/ddaa071
Annekatrien Boel 1, 2 , Joyce Burger 3, 4 , Marine Vanhomwegen 1 , Aude Beyens 1, 5 , Marjolijn Renard 1 , Sander Barnhoorn 3, 4 , Christophe Casteleyn 6 , Dieter P Reinhardt 7 , Benedicte Descamps 8 , Christian Vanhove 8 , Ingrid van der Pluijm 3, 4, 9 , Paul Coucke 1 , Andy Willaert 1 , Jeroen Essers 3, 4, 9, 10 , Bert Callewaert 1
Affiliation  

Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicated GLUT10 in the transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations did not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in mouse. Gulo;Slc2a10 double knock-out mice showed mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. Transforming growth factor beta signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 double knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.

中文翻译:

抗坏血酸合成缺陷的 Slc2a10 敲除小鼠重现了动脉迂曲综合征的各个方面,并表现出线粒体呼吸缺陷。

动脉迂曲综合征(ATS)是一种隐性遗传的结缔组织疾病,主要表现为大动脉迂曲和动脉瘤形成。ATS由丧失功能的突变引起SLC2A10,编码葡萄糖转运GLUT10。以前的研究表明 GLUT10 与脱氢抗坏血酸(抗坏血酸 (AA) 的氧化形式)的转运有关。携带纯合Slc2a10错义突变的小鼠模型没有重现人类表型。由于与人类相比,小鼠能够在细胞内合成 AA,因此我们生成了一种新的 ATS 小鼠模型,该模型缺乏Slc2a10Gulo,它编码 L-古洛糖酸内酯氧化酶,一种催化小鼠 AA 生物合成最后一步的酶。Gulo;Slc2a10双基因敲除小鼠表现出轻微的表型异常,而单基因敲除对照组不存在这种异常。虽然Gulo;Slc2a10双基因敲除小鼠并未完全模拟人类 ATS,但组织学和免疫细胞化学分析显示细胞外基质形成受损。转化生长因子 β 信号保持不变,而来自Gulo 的平滑肌细胞中的线粒体功能受到损害;Slc2a10双基因敲除小鼠。总而言之,我们的数据增加了 ATS 是一种抗坏血酸区室化障碍的证据,但在人类中观察到的表型背后的其他因素仍有待确定。
更新日期:2020-04-20
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