Milosavljevic Sofia, Glinton Kevin E, Li Xiqi, Medeiros Cláudia, Gillespie Patrick, Seavitt John R, Graham Brett H, Elsea Sarah H
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Harvard Medical School, Boston, MA 02215, USA.
Metabolites. 2022 Apr 14;12(4):351. doi: 10.3390/metabo12040351.
Though biallelic variants in are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a -deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder.
虽然已知[具体基因]的双等位基因变异会导致严重的脑病，但其发病机制仍知之甚少。SLC13A5蛋白缺乏会减少柠檬酸盐向细胞内的转运。尽管在SLC13A5缺乏症患者中，这些紊乱的生化指标并不一致，但脂肪酸合成和能量产生的下游异常已有描述。为了研究与SLC13A5相关的疾病，我们对一种[基因]缺陷小鼠模型的肝脏、大脑和血清进行了非靶向代谢分析。代谢组学数据采用连点法（CTD）进行分析，并与SLC13A5缺乏症患者的血浆和脑脊液代谢组学数据进行比较。纯合缺失等位基因的小鼠在所有检测组织中的脂肪酸、胆汁酸和能量代谢物均出现紊乱。进一步分析表明，对于其中几种分子，它们在敲除小鼠体内的相对组织浓度比值差异很大，这表明Slc13a5的缺乏会影响组织间代谢物的生物合成和通量。在患者生物流体中也观察到了类似的结果，表明参与能量、脂肪酸、核苷酸和胆汁酸代谢的分子的转运和/或通量发生了改变。SLC13A5缺乏可能导致比以前认识到的更广泛的代谢失调状态，特别是在脂质合成、储存和代谢方面，支持将SLC13A5缺乏视为一种脂质紊乱疾病。
