title: Human equilibrative nucleoside transporter-3 (hENT3) spectrum disorder mutations impair nucleoside transport, protein localization, and stability.
abstract: Accumulating evidence reveals that sole mutations in hENT3 cause a spectrum of human genetic disorders. Among these include H syndrome, characterized by scleroderma, hyperpigmentation, hypertrichosis, hepatomegaly, cardiac abnormalities and musculoskeletal deformities, pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndrome, characterized by autoantibody-negative diabetes mellitus and skin deformities, familial Rosai-Dorfman disease, characterized by short stature, familial histiocytosis and sinus histiocytosis with massive lymphadenopathy (SHML), characterized by severe tissue infiltration of immune cells and swollen lymph nodes. hENT3 spectrum disorders share a common mutation and share overlapping clinical manifestations that display many intriguing resemblances to mitochondrial and lysosomal disorders. Although earlier studies identify hENT3 as a mitochondrial and a lysosomal nucleoside transporter, the precise connections between hENT3 and the pathophysiology of these disorders remain unresolved. In this study, we performed functional and biochemical characterization of these mutations in hENT3. We report severe reductions/losses of hENT3 nucleoside transport functions of hENT3 syndrome mutants. In addition to transport alterations, we provide evidence for possible loss of hENT3 functions in all H and pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndromes due to either mistrafficking or altered stability of mutant hENT3 proteins.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kang
authors.forename: Ah Hyun
authors.initials: AH
authors.lastname: Jun
authors.forename: Yangzom Doma
authors.initials: YD
authors.lastname: Bhutia
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Govindarajan
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D004194:Disease / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005998:Glycine; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D041681:NIH 3T3 Cells; D033703:Nucleoside Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism*; D011487:Protein Conformation; D055550:Protein Stability; D021381:Protein Transport
chemical_list: D033703:Nucleoside Transport Proteins; D009705:Nucleosides; C501424:SLC29A3 protein, human; D000241:Adenosine; D005998:Glycine