PDF(Pubmed)
Abstract：
Classic galactosemia (CG) arises from loss-of-function mutations in the Galt gene, which codes for the enzyme galactose-1-phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low-galactose diet, GALT\'s substrate galactose-1-phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides-galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1-were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.
摘要：
经典半乳糖血症（CG）是由Galt基因的功能丧失突变引起的，它编码半乳糖-1-磷酸尿嘧啶基转移酶（GALT），半乳糖代谢的中心成分。与CG相关的新生儿死亡可以通过半乳糖饮食限制来预防，但是几十年来，人们已经知道，限制半乳糖的摄入并不是一种治疗方法，而且患者往往会有持续的并发症。即使是低半乳糖饮食，GALT的底物半乳糖-1-磷酸（Gal1P）升高，一种假设是Gal1P升高是病理的驱动因素。在这里，我们显示Gal1P水平在Galt突变小鼠中高于野生型（WT），而Galt的双重突变体和编码半乳糖激酶1（Galk1）的基因小鼠的Gal1P水平正常。这表明GALK1对于CG中升高的Gal1P是必需的。解释病理学的另一个假设是不能代谢半乳糖导致蛋白质或脂质的半乳糖基化减少或破坏。我们的研究表明，与WT相比，脑苷脂-半乳糖神经酰胺24：1，硫酸脂24：1和葡萄糖神经酰胺24：1的子集水平略有降低。相比之下,神经节苷脂没有改变。观察到的这些24：1脑苷脂的减少可能与CG的临床病理有关，由于脑苷脂半乳糖神经酰胺是髓磷脂的重要结构成分，24:1的物种是髓鞘中最丰富的，和白质的不规则性，髓鞘是其中的一个组成部分，在CG患者中观察到。因此,脑苷脂的产生受损可能是脑损伤的一个促成因素，脑损伤是人类疾病的常见临床特征。
