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

doi:10.1038/10372

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 journal › Article › peer-review

250 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 language	English
Pages (from-to)	300-304
Number of pages	5
Journal	Nature Genetics
Volume	22
Issue number	3
DOIs	https://doi.org/10.1038/10372
State	Published - Jul 1999
Externally published	Yes

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).

Funding

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).

Funders	Funder number
Israeli Academy of Sciences
Israeli Ministry of Sciences
Pittsburgh Technion Research Foundation
Juvenile Diabetes Research Foundation International

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/10372

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title = "Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness",

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.",

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

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AU - Szargel, Raymonde

AU - McDonald, Louise

AU - Shalata, Adel

AU - Nosaka, Kazuto

AU - Gregory, Simon

AU - Cohen, Nadine

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

Abstract

Bibliographical note

Funding

UN SDGs

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