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

Hum Mol Genet. 2002 Nov 1;11(23):2951-60. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anemia, Megaloblastic / genetics*
  • Anemia, Megaloblastic / pathology
  • Animals
  • Bone Marrow / pathology
  • Brain / metabolism
  • DNA Primers / chemistry
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / pathology
  • Erythrocytes / metabolism
  • Gene Deletion*
  • Gene Targeting
  • Glucose / metabolism
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • Insulin / metabolism
  • Male
  • Membrane Transport Proteins / deficiency
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Pancreas / metabolism
  • Pancreas / pathology
  • Polymerase Chain Reaction
  • Thiamine / metabolism
  • Thiamine / pharmacology


  • DNA Primers
  • Insulin
  • Membrane Transport Proteins
  • Slc19a2 protein, mouse
  • Glucose
  • Thiamine