SLC29A3 Gene: ENT3 Transporter - Function, Mutations, and Associated Diseases

SLC29A3 encodes the equilibrative nucleoside transporter 3 (ENT3), a member of the SLC29 family of transporters. ENT3 mediates the bidirectional transport of nucleosides and nucleobases across intracellular membranes, particularly lysosomes and mitochondria. It plays a critical role in nucleoside salvage, cellular energy homeostasis, and immune regulation. Loss-of-function mutations in SLC29A3 cause a spectrum of autosomal recessive disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), and familial histiocytosis with sensorineural deafness (FHSD).

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Nucleoside salvage pathway (Reactome: R-HSA-73627)

• Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (Reactome: R-HSA-83936)

• Lysosomal nucleoside transport (Reactome: R-HSA-425397)

ENT3 is a 475-amino acid protein with 11 transmembrane domains. It localizes to lysosomal and mitochondrial membranes, functioning as a pH-dependent equilibrative transporter for purine and pyrimidine nucleosides. The protein contains a conserved N-terminal dileucine motif required for lysosomal targeting. Defects in ENT3 disrupt nucleoside recycling, leading to lysosomal nucleoside accumulation and activation of inflammatory pathways, particularly in macrophages and dendritic cells.