Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
Institut de Recerca Sant Joan de Déu (IR SJD), Esplugues de Llobregat, 08950 Barcelona, Spain.
Int J Mol Sci. 2022 Aug 7;23(15):8770. doi: 10.3390/ijms23158770.
The proper regulation of nucleotide pools is essential for all types of cellular functions and depends on de novo nucleotide biosynthesis, salvage, and degradation pathways. Despite the apparent essentiality of these processes, a significant number of rare diseases associated with mutations in genes encoding various enzymes of these pathways have been already identified, and others are likely yet to come. However, knowledge on genetic alterations impacting on nucleoside and nucleobase transporters is still limited. At this moment three gene-encoding nucleoside and nucleobase transporter proteins have been reported to be mutated in humans, , , and , impacting on the expression and function of ENT1, ENT3, and CNT1, respectively. ENT1 alterations determine Augustine-null blood type and cause ectopic calcification during aging. ENT3 deficiency translates into various clinical manifestations and syndromes, altogether listed in the OMIM catalog as histiocytosis-lymphoadenopathy plus syndrome (OMIM#602782). CNT1 deficiency causes uridine-cytidineuria (URCTU) (OMIM#618477), a unique type of pyrimidineuria with an as yet not well-known clinical impact. Increasing knowledge on the physiological, molecular and structural features of these transporter proteins is helping us to better understand the biological basis behind the biochemical and clinical manifestations caused by these deficiencies. Moreover, they also support the view that some metabolic compensation might occur in these disturbances, because they do not seem to significantly impact nucleotide homeostasis, but rather other biological events associated with particular subtypes of transporter proteins.
核苷酸池的适当调节对于所有类型的细胞功能都是必不可少的，这取决于从头核苷酸生物合成、补救和降解途径。尽管这些过程显然是必需的，但已经确定了许多与这些途径中各种酶的基因突变相关的罕见疾病，而且可能还有其他疾病尚未被发现。然而，关于影响核苷和碱基转运蛋白的遗传改变的知识仍然有限。目前，已经报道了三种编码核苷和碱基转运蛋白的基因发生突变，分别为、、和，分别影响 ENT1、ENT3 和 CNT1 的表达和功能。ENT1 改变决定了 Augustine 无血型，并导致衰老时异位钙化。ENT3 缺乏导致各种临床表现和综合征，统称为组织细胞增生症-淋巴结病综合征（OMIM#602782）。CNT1 缺乏导致尿嘧啶-胞苷尿症（URCTU）（OMIM#618477），这是一种独特的嘧啶尿症，其临床影响尚不清楚。对这些转运蛋白的生理、分子和结构特征的深入了解有助于我们更好地理解这些缺乏症引起的生化和临床表现背后的生物学基础。此外，它们还支持这样一种观点，即这些紊乱可能会发生一些代谢代偿，因为它们似乎不会对核苷酸稳态产生显著影响，而是与特定转运蛋白亚型相关的其他生物学事件有关。
