Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice.

Thiamin-responsive megaloblastic anemia syndrome (TRMA) is characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. Mutations in the thiamin transporter gene SLC19A2 cause TRMA. 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. Erythrocytes from Slc19a2(-/-) mice lacked the high-affinity component of thiamin transport. On a thiamin-free diet, Slc19a2(-/-) mice developed diabetes mellitus with reduced insulin secretion and an enhanced response to insulin. The diabetes mellitus resolved after 6 weeks of thiamin repletion. Auditory-evoked brainstem response thresholds were markedly elevated in Slc19a2(-/-) mice on a thiamin-free diet, but were normal in wild-type mice treated on that diet as well as thiamin-fed Slc19a2(-/-) mice. Bone marrows from thiamin-deficient Slc19a2(-/-) mice were abnormal, with a megaloblastosis affecting the erythroid, myeloid and megakaryocyte lines. 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.