Journal Article

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

Kimihiko Oishi, Susanna Hofmann, George A. Diaz, Tartania Brown, Deepa Manwani, Lily Ng, Randy Young, Helen Vlassara, Yiannis A. Ioannou, Douglas Forrest and Bruce D. Gelb

in Human Molecular Genetics

Volume 11, issue 23, pages 2951-2960
Published in print November 2002 | ISSN: 0964-6906
Published online November 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.23.2951
Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice

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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.

Journal Article.  5533 words.  Illustrated.

Subjects: Genetics and Genomics

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