Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.

中文翻译：

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深入的表型揭示了在mut型甲基丙二酸尿症的半合子敲入小鼠模型（Mut-ko / ki）中常见和新颖的疾病症状。

分离的甲基丙二酸尿症（MMAuria）主要是由甲基丙二酰辅酶A突变酶（MMUT或MUT）缺乏引起的。从生化角度看，MUT缺乏会导致甲基丙二酸（MMA），丙酰肉碱（C3）和其他代谢物的积累。患者经常表现出嗜睡，无法ive壮成长和代谢失代偿，从而导致昏迷甚至死亡，长期以来经常发现肾脏和神经功能受损。在这里，我们报道了一个半合子小鼠模型，该模型结合了Mut的敲入（ki）错义等位基因与敲除（ko）等位基因（Mut-ko / ki小鼠），从第12天开始喂食51％蛋白质生命，构成MMAuria的定制模型。在这种饮食下 突变小鼠表现出明显的代谢表型，与同窝对照相比，其血液中的MMA和C3含量急剧增加（Mut-ki / wt）。使用这种定制的小鼠模型，我们进行了标准化的表型筛选，以评估与此强代谢状况相关的全身损伤。我们发现Mut-ko / ki小鼠表现出MMAuria的常见临床表现，包括明显的ive体衰竭，轻度神经系统和肾脏功能障碍的征兆以及肝脏中的变性形态变化，以及诸如心血管和血液学异常之类的症状欠佳的症状。 。分析还揭示了迄今为止未知的疾病特征，包括低骨密度，焦虑相关行为和卵巢萎缩。