Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness

Valentina Labay, Tal Raz, Dana Baron, Hanna Mandel, Hawys Williams, Timothy Barrett, Raymonde Szargel, Louise McDonald, Adel Shalata, Kazuto Nosaka, Simon Gregory, Nadine Cohen

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

Thiamine-responsive megaloblastic anaemia (TRMIA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM intervals. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.

Original languageEnglish
Pages (from-to)300-304
Number of pages5
JournalNature Genetics
Volume22
Issue number3
DOIs
StatePublished - Jul 1999
Externally publishedYes

Bibliographical note

Funding Information:
We thank the families; the Sanger Centre Mapping, Sequencing and Analysis teams, particularly C. Bird, for the finishing of PAC 206D15; S. Rhodes for the further analysis of the finished sequence; and E. Sprecher for critical reading of the manuscript. This work was supported by grants from the Juvenile Diabetes Foundation International, the Israeli Academy of Sciences and the Pittsburgh Technion Research Foundation (N.C.). V.L. is recipient of a post-doctoral fellowship from the Juvenile Diabetes Foundation International and from the Israeli Ministry of Sciences (in part).

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