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

• Published in: Human molecular genetics 2002-11, Vol.11 (23), p.2951-2960
• Main Authors: Oishi, Kimihiko, Hofmann, Susanna, Diaz, George A., Brown, Tartania, Manwani, Deepa, Ng, Lily, Young, Randy, Vlassara, Helen, Ioannou, Yiannis A., Forrest, Douglas, Gelb, Bruce D.
• Format: Article
• Language: English
• Subjects: Anemia, Megaloblastic - genetics; Anemia, Megaloblastic - pathology; Animals; Biological and medical sciences; Bone Marrow - pathology; Brain - metabolism; Cell physiology; Complex syndromes; Diabetes Mellitus - genetics; Diabetes Mellitus - pathology; DNA Primers - chemistry; Erythrocytes - metabolism; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Targeting; Glucose - metabolism; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Insulin - metabolism; Male; Medical genetics; Medical sciences; Membrane and intracellular transports; Membrane Transport Proteins - deficiency; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, Knockout; Molecular and cellular biology; Pancreas - metabolism; Pancreas - pathology; Polymerase Chain Reaction; Thiamine - metabolism; Thiamine - pharmacology
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/11.23.2951

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.