Disease relevance of Slc19a2

• On a thiamin-free diet, Slc19a2(-/-) mice developed diabetes mellitus with reduced insulin secretion and an enhanced response to insulin [1].
• A mouse model of thiamin-responsive megaloblastic anemia (diabetes mellitus, deafness, megaloblastic anemia) lacking functional Slc19a2 has been generated and unexpectedly found to have a male-specific sterility phenotype [2].
• Male infertility and thiamine-dependent erythroid hypoplasia in mice lacking thiamine transporter Slc19a2 [3].

High impact information on Slc19a2

• Bone marrows from thiamin-deficient Slc19a2(-/-) mice were abnormal, with a megaloblastosis affecting the erythroid, myeloid and megakaryocyte lines [1].
• Erythrocytes from Slc19a2(-/-) mice lacked the high-affinity component of thiamin transport [1].
• To generate a mouse model of TRMA, we developed an Slc19a2 targeting construct using transposon-mediated mutagenesis and disrupted the gene through homologous recombination in embryonic stem cells [1].
• Our findings indicate that p53 may be involved in maintaining thiamine homeostasis through transactivation of THTR-1 [4].
• These data suggest that RFC1 may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia [5].

Biological context of Slc19a2

• Thus, Slc19a2(-/-) mice have provided new insights into the TRMA disease pathogenesis and will provide a tool for studying the role of thiamin homeostasis in diabetes mellitus more broadly [1].
• The Slc19a2 cDNA contained a 1494-bp open-reading frame, and had 5'- and 3'-untranslated regions of 189 and 1857 bp, respectively [6].
• The Slc19a2 gene spanned 16.3 kb and was organized into six exons, a gene structure conserved with the human orthologue [6].
• Comparison of the Slc19a2 amino acid sequence with those of the other known SLC19A solute carriers highlighted interesting patterns of conservation and divergence in various domains, allowing insight into potential structure-function relationships [6].
• We localized the Slc19a2 gene to mouse chromosome 1, a region syntenic to human chromosome 1q23 that contains the TRMA locus [7].

Anatomical context of Slc19a2

• Slc19a2 -/- mice on a pure 129/Sv background develop reticulocytopenia after two weeks on thiamine-depleted chow with a virtual absence of reticulocytes in the peripheral blood (0.12% knockout vs. 2.58% wild type, P=0.0079) [3].
• Contrary to human TRMA syndrome, we see no evidence of megaloblastosis or ringed sideroblasts in the bone marrow of Slc19a2 -/- mice in thiamine-replete or thiamine-deficient dietary states [3].
• Immunohistochemistry studies indicate that Slc19a2 is expressed on the cell surface and intracellularly, and is specifically localized to a subpopulation of cells in cochlea, small intestine, and pancreas [7].
• CONCLUSIONS: Taken collectively, these results suggest that the G172D mutation presumably misfolded THTR-1 protein that fails to undergo a complete glycosylation, is retained in the Golgi-ER compartment and thereby cannot be targeted to the plasma membrane [8].
• RESULTS: The mutant THTR-1 protein was undetectable in transfected cells grown at 37 degrees C but was readily expressed in transfected cells cultured at 28 degrees C, thereby allowing for further biochemical and functional analysis [8].

Associations of Slc19a2 with chemical compounds

• Consistently, either treatment with tunicamycin or substitution of the THTR-1 consensus N-glycosylation acceptor asparagine 63 with glutamine, abolished its glycosylation and plasma membrane targeting [8].
• We also explored the impact on methotrexate (MTX) transport activity of a homologous missense D88H mutation in the human RFC, a close homologue of THTR1 [9].

Analytical, diagnostic and therapeutic context of Slc19a2

• Western blot analysis of mouse tissues reveals a wide distribution of Slc19a2 protein [7].
• The identification of the mouse Slc19a2 cDNA and genomic sequences will facilitate the generation of an animal model of TRMA, permitting future studies of disease pathogenesis [6].

References