Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice.
Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice.
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组织特异性 FAH 缺乏会改变小鼠的睡眠-觉醒模式并导致慢性酪氨酸血症。
DOI：
10.1073/pnas.1904485116
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发表时间：
2019
影响因子：
11.1
通讯作者：
Takahashi,JosephS
中科院分区：
文献类型：
--
作者：
Yang,Shuzhang;Siepka,SandraM;Cox,KimberlyH;Kumar,Vivek;deGroot,Marleen;Chelliah,Yogarany;Chen,Jun;Tu,Benjamin;Takahashi,JosephS
富马酰乙酰乙酸水解酶（FAH）是酪氨酸激酶的最后一个酶，FAH基因突变与人类遗传性酪氨酸血症I型（HT 1或TYRSN 1）有关。在N-乙基-N-亚硝基脲诱变小鼠的行为筛选中，我们鉴定了一种我们命名为“swingshift”（swst，MGI：3611216）的突变系，其Fah中的非同义点突变（N68 S）导致睡眠-觉醒模式的年龄依赖性破坏。与野生型或杂合子小鼠相比，突变纯合子小鼠的活动开始较早（熄灯前几小时），总活动和体重减少。尽管异常行为夹带到光暗周期，有没有差异的突变小鼠的中央时钟的周期或阶段，表明一个缺陷的视交叉上核下游。有趣的是，随着小鼠年龄的增长，这些行为表型变得更温和，并且通过给予NTBC [2-（2-硝基-4-三氟甲基苯甲酰基）-1，3-环己二酮]完全拯救，NTBC是4-羟苯基丙酮酸双加氧酶的抑制剂，其位于FAH的上游。从机理上讲，突变对FAH的酶活性没有影响，而是促进了突变蛋白的降解。这导致纯合子小鼠肝脏和肾脏（但不是大脑或成纤维细胞）中FAH蛋白水平和酶活性降低。此外，纯合子小鼠的血浆酪氨酸增加，而蛋氨酸、苯丙氨酸或琥珀酰丙酮没有增加，这表明突变体提供了轻度慢性HT 1的模型。
Fumarylacetoacetate hydrolase (FAH) is the last enzyme in tyrosine catabolism, and mutations in theFAHgene are associated with hereditary tyrosinemia type I (HT1 or TYRSN1) in humans. In a behavioral screen ofN-ethyl-N-nitrosourea mutagenized mice we identified a mutant line which we named “swingshift” (swst, MGI:3611216) with a nonsynonymous point mutation (N68S) inFahthat caused age-dependent disruption of sleep–wake patterns. Mice homozygous for the mutation had an earlier onset of activity (several hours before lights off) and a reduction in total activity and body weight when compared with wild-type or heterozygous mice. Despite abnormal behavioral entrainment to light–dark cycles, there were no differences in the period or phase of the central clock in mutant mice, indicating a defect downstream of the suprachiasmatic nucleus. Interestingly, these behavioral phenotypes became milder as the mice grew older and were completely rescued by the administration of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione], an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, which is upstream of FAH. Mechanistically, theswstmutation had no effect on the enzymatic activity of FAH, but rather promoted the degradation of the mutant protein. This led to reduced FAH protein levels and enzymatic activity in the liver and kidney (but not the brain or fibroblasts) of homozygous mice. In addition, plasma tyrosine—but not methionine, phenylalanine, or succinylacetone—increased in homozygous mice, suggesting thatswstmutants provide a model of mild, chronic HT1.