A novel mutation in Slc2a4 as a mouse model of fatigue.
A novel mutation in Slc2a4 as a mouse model of fatigue.
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Slc2a4 的新突变可作为小鼠疲劳模型。
DOI：
10.1111/gbb.12578
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Takahashi,JosephS
中科院分区：
文献类型：
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作者：
deGroot,MarleenHM;Castorena,CarlosM;Cox,KimberlyH;Kumar,Vivek;Mohawk,JenniferA;Ahmed,NewazI;Takahashi,JosephS
慢性疲劳是一种影响广泛的衰弱性疾病，但缺乏有效的治疗策略。新的遗传小鼠疲劳模型对于研究其潜在的生理机制和测试治疗和干预措施可能是非常宝贵的。在对inN -乙基- N -亚硝基脲诱变的C57BL/6J小鼠的自愿跑轮行为筛选中，我们发现了两种低体重和异常跑轮模式提示疲劳表型的小鼠。这些品系的受影响后代的日常活动水平较低，并表现出低幅度的昼夜节律改变。他们的异常行为表现为在明暗周期的黑暗阶段频繁中断和不活动，而在休息或光明阶段活动水平增加。策略杂交后代的行为表型表达符合隐性遗传模式。表型异常图谱显示与1号染色体上的单个位点相关，全外显子组测序发现编码GLUT4胰岛素反应性葡萄糖转运蛋白的slc2a4基因存在单点突变。单核苷酸变化（A‐T，我们命名为“twiggy”）位于第10外显子的远端，导致过早停止（Y440*）。额外的代谢表型证实，这些小鼠再现了GLUT4敲除小鼠的表型。然而，据我们所知，这是该基因的突变第一次被证明会导致一般行为模式的广泛改变。这些发现表明，GLUT4可能参与昼夜节律行为异常，并可能为人类疲劳提供见解。
Chronic fatigue is a debilitating disorder with widespread consequences, but effective treatment strategies are lacking. Novel genetic mouse models of fatigue may prove invaluable for studying its underlying physiological mechanisms and for testing treatments and interventions. In a screen of voluntary wheel‐running behavior inN‐ethyl‐N‐nitrosourea mutagenized C57BL/6J mice, we discovered two lines with low body weights and aberrant wheel‐running patterns suggestive of a fatigue phenotype. Affected progeny from these lines had lower daily activity levels and exhibited low amplitude circadian rhythm alterations. Their aberrant behavior was characterized by frequent interruptions and periods of inactivity throughout the dark phase of the light‐dark cycle and increased levels of activity during the rest or light phase. Expression of the behavioral phenotypes in offspring of strategic crosses was consistent with a recessive inheritance pattern. Mapping of phenotypic abnormalities showed linkage with a single locus on chromosome 1, and whole exome sequencing identified a single point mutation in theSlc2a4gene encoding the GLUT4 insulin‐responsive glucose transporter. The single nucleotide change (A‐T, which we named “twiggy”) was in the distal end of exon 10 and resulted in a premature stop (Y440*). Additional metabolic phenotyping confirmed that these mice recapitulate phenotypes found in GLUT4 knockout mice. However, to the best of our knowledge, this is the first time a mutation in this gene has been shown to result in extensive changes in general behavioral patterns. These findings suggest that GLUT4 may be involved in circadian behavioral abnormalities and could provide insights into fatigue in humans.