Deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene was identified in probands with autism spectrum disorder (ASD). TMLHE encodes the first enzyme in carnitine biosynthesis, N6-trimethyllysine dioxygenase (TMLD). Researchers have suggested that carnitine depletion could be important for the development of ASD and cognitive, locomotor and social dysfunctions, but previous findings have been inconclusive regarding the specific role of endogenous carnitine. We developed a mouse knockout model with constitutive TMLD enzyme inactivation that exhibited a significant decrease in the carnitine by more than 90% compared to wild-type (WT) mice. However, we did not observe any significant social, cognitive, or repetitive-behavior changes associated with ASD in the knockout mice; muscle strength and coordination were also not affected. In addition, the life expectancy of knockout mice was similar to that of WT mice. In conclusion, knockout of Tmlh in mice does not induce an ASD phenotype or motor dysfunction despite extremely low carnitine and gamma-butyrobetaine concentrations. Moreover, inactivation of TMLD does not induce a phenotype similar to previously described primary carnitine deficiency; indeed, our results showed that low levels of carnitine sustained adequate energy production, muscle function and social behavior in mice.

中文翻译：

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尽管肉碱水平较低，但敲除小鼠 Tmlhe 与自闭症谱系障碍表型或运动功能障碍无关

在患有自闭症谱系障碍 (ASD) 的先证者中发现了三甲基赖氨酸羟化酶 epsilon (TMLHE) 基因的外显子 2 缺失。TMLHE 编码肉碱生物合成中的第一种酶，N6-三甲基赖氨酸双加氧酶 (TMLD)。研究人员认为，肉碱消耗对于自闭症谱系障碍以及认知、运动和社会功能障碍的发展可能很重要，但之前的研究结果对于内源性肉碱的具体作用尚无定论。我们开发了一种具有组成型 TMLD 酶失活的小鼠模型，与野生型 (WT) 小鼠相比，该模型的肉毒碱显着减少了 90% 以上。然而，我们没有在基因敲除小鼠中观察到与 ASD 相关的任何显着的社交、认知或重复行为变化。肌肉力量和协调性也没有受到影响。此外，基因敲除小鼠的预期寿命与WT小鼠相似。总之，尽管肉碱和γ-丁甜菜碱浓度极低，但敲除小鼠中的 Tmlh 不会诱导 ASD 表型或运动功能障碍。此外，TMLD 失活不会诱导类似于先前描述的原发性肉碱缺乏症的表型；事实上，我们的结果表明，低水平的肉碱可以维持小鼠充足的能量产生、肌肉功能和社会行为。