title: The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families.
abstract: Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder with a triad of symptoms: megaloblastic anemia, deafness, and non-type 1 diabetes mellitus. Occasionally, cardiac abnormalities and abnormalities of the optic nerve and retina occur as well. Patients with TRMA often respond to treatment with pharmacological doses of thiamine. Recently, mutations were found in patients with TRMA in a thiamine transporter gene (SLC19A2). We here describe the mutations found in eight additional families. We found four novel mutations and three that were previously described. Of the novel ones, one is a nonsense mutation in exon 1 (E65X), two are missense mutations in exon 2 (S142F, D93H), and another is a mutation in the splicing donor site at the 5' end of intron 4 (C1223+1G>A). We also summarize the state of knowledge on all mutations found to date in TRMA patients. SLC19A2 is the first thiamine transporter gene to be described in humans. Reviewing the location and effect of the disease causing mutations can shed light on the way the protein functions and suggest ways to continue its investigation.
authors.affiliation: Department of Genetics, Tamkin Human Molecular Genetics Research Facility, Technion-Israel Institute of Technology, Bruce Rappaport Faculty of Medicine, Haifa, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Raz
authors.forename: V
authors.initials: V
authors.lastname: Labay
authors.forename: D
authors.initials: D
authors.lastname: Baron
authors.forename: R
authors.initials: R
authors.lastname: Szargel
authors.forename: Y
authors.initials: Y
authors.lastname: Anbinder
authors.forename: T
authors.initials: T
authors.lastname: Barrett
authors.forename: W
authors.initials: W
authors.lastname: Rabl
authors.forename: M B
authors.initials: MB
authors.lastname: Viana
authors.forename: H
authors.initials: H
authors.lastname: Mandel
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.forename: J M
authors.initials: JM
authors.lastname: Cayuela
authors.forename: N
authors.initials: N
authors.lastname: Cohen
mesh_terms: D000483:Alleles; D000749:Anemia, Megaloblastic / Q000188:drug therapy / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns; D008297:Male; D026901:Membrane Transport Proteins; D009154:Mutation; D010375:Pedigree; D015183:Restriction Mapping / Q000379:methods; D013831:Thiamine / Q000627:therapeutic use*
chemical_list: D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D013831:Thiamine