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.

Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE

“…Our results suggested that in the context of MNGIE, mitochondrial and lysosomal damage coexist and reinforce each other: on the one hand, defects in mitochondrial energy metabolism increase the generation of ROS, which may in turn increase the permeability of lysosomal membranes; on the other hand, lysosomal dysfunction impedes the normal clearance of mitochondria, leading to the persistent presence of abnormal mitochondria with mtDNA defects. Similarly, defects in the ENT3 protein have been found to simultaneously lead to mitochondrial damage and lysosomal dysfunction, resulting in an accumulation of mitochondrial redundancy, increased ROS and increased lysosomal volume [ 65 , 66 ]. The mechanism behind this phenomenon may be consistent with the mechanism of mitochondrial and lysosomal nucleoside accumulation caused by TP deficiency, as studies have shown that ENT3 is localized not only in lysosomes but also in mitochondria [ 60 ].…”

How Cryo-EM Has Expanded Our Understanding of Membrane Transporters

“…The equilibrative nucleoside transporters are transporters belonging to the solute carrier transporter family SLC29 ( Baldwin et al, 2004 ; Young et al, 2013 ; Pastor-Anglada et al, 2022 ). As their name implies, equilibrative nucleoside transporters are major players in the transport of nucleobases (adenine) and nucleosides (adenosine) through a rocker-switch mechanism ( Fig.…”

“…The Augustine blood type, characterized by SLC29A1 mutations, was established as a blood group in 2015, although the antigen was first identified in 1967 ( Daniels et al, 2015 ; Daniels, 2022 ). SLC29A1-null individuals appear healthy, although pseudogout and ectopic calcification during aging have been reported ( Daniels et al, 2015 ; Pastor-Anglada et al, 2022 ). SLC29A1 deficiency has not been listed in the OMIM catalog at present.…”

“…The equilibrative nucleoside transporters, or ENTs, are transporters belonging to the solute carrier transporter family SLC29 (Baldwin et al, 2004;Young et al, 2013;Pastor-Anglada et al, 2022). As their name implies, ENTs are major players in the transport of nucleobases (adenine) and nucleosides (adenosine) through a rockerswitch mechanism (Figure 2), whereby the two halves of the transporter undergo rigid body rearrangements to alternate solvent access of the transporter cavity to either side of the lipid bilayer (Wright and Lee, 2019, 2022Qureshi et al, 2020;Drew et al, 2021).…”

Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease and Disease Treatment

“…The review “Inborn Errors of Nucleoside Transporter (NT)-Encoding Genes ( SLC28 and SLC29 )” by Pastor-Anglada et al [ 1 ] summarizes the genetic alterations impacting nucleoside and nucleobase transporters, focusing on Solute Carrier ( SLC ) 29A1 , SLC29A3 , and SLC28A1 , and underlines the relationships between transporter function and pathology.…”