title: Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice.
abstract: 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.
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Oishi
authors.forename: Susanna
authors.initials: S
authors.lastname: Hofmann
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.forename: Tartania
authors.initials: T
authors.lastname: Brown
authors.forename: Deepa
authors.initials: D
authors.lastname: Manwani
authors.forename: Lily
authors.initials: L
authors.lastname: Ng
authors.forename: Randy
authors.initials: R
authors.lastname: Young
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
authors.forename: Yiannis A
authors.initials: YA
authors.lastname: Ioannou
authors.forename: Douglas
authors.initials: D
authors.lastname: Forrest
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000749:Anemia, Megaloblastic / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001921:Brain / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism; D017353:Gene Deletion; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D013831:Thiamine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D007328:Insulin; D026901:Membrane Transport Proteins; C492292:Slc19a2 protein, mouse; D005947:Glucose; D013831:Thiamine