Inborn Errors of Nucleoside Transporter (NT)-Encoding Genes (SLC28 and SLC29)

Abstract

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, SLC29A1, SLC29A3, and SLC28A1, 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.

Keywords: genetics; nucleosides; rare diseases; transporters.

Figure 1

Chronogram of the discovery of rare diseases caused by mutations in genes encoding nucleotide metabolism-related proteins. Nucleoside transporters (ENT3, ENT1, and CNT1) are boxed. Full names of all enzyme acronyms are introduced in the text.

Figure 2

Nucleoside transporter expression patterns and substrate selectivity. Heat-maps showing the tissue expression of SLC29A1 (ENT1), SLC29A3 (ENT3) and SLC28A1 (CNT1) at the mRNA (A) and protein (B) levels; data obtained from the EMBL-EBI database.

Figure 3

ENT1 functions in nucleotide metabolism. (A) Schematic representation of adenosine (A) translocation and signaling. Adenosine activation of P1 receptors (i.e., A2B) promotes osteogenic differentiation of mesenchymal stem cells. Intracellular cAMP levels are modulated by ENT1-associated adenosine translocation and also by MRP4 cAMP efflux. In turn, cAMP homeostasis is critical for erythropoiesis regulation. (B) Nucleoside uptake at the plasma membrane is mediated by ENT1 and ENT2 homo and hetero-oligomeric complexes. ENT1 has been reported to translocate nucleosides and deoxynucleosides in mitochondria. In ENT1 null cells, deoxynucleoside supply to mitochondria may be maintained by ENT3 function, although the proven functional expression of an unknown deoxynucleotide transporter (?) may be the best compensatory mechanism to maintain mitochondrial deoxynucleotide pools for DNA replication.

Figure 4

ENT3 functions in lysosomes. ENT3 is proposed to regulate autophagy by modulating adenosine (A) release from the lysosomes into the cytosol, which contributes to AMPK activation and the regulation of the AMPK–mTOR–ULK axis. Additionally, ENT3 has been recently proposed as a low-affinity bile acid transporter at pH 5.5, contributing to ER stress regulation.

Figure 5

CNT1 function and presence at the plasma membrane contribute to pyrimidine reabsorption in the kidney. (A) CNT1 is expressed at the apical plasma membrane of kidney proximal tubule epithelial cells, where it is responsible for pyrimidine reabsorption (C, cytidine; U, uridine; T; thymidine). (B) N-linked glycosylation contributes to CNT1 plasma membrane localization. This post-translational modification of the protein is partially impaired in variants p.R510C and p.R561Q, causative of URCTU. CNT1 also functions as a transceptor. Besides pyrimidine translocation, it can also induce changes in signaling pathways (arrows, see text), regardless of its transporter function. Variant p.S546P lacks this translocation ability, but is properly located at the plasma membrane and retains some wild type transceptor functions.