Loss-of-Function Mutation in Thiamine Transporter 1 in a Family With Autosomal Dominant Diabetes.

Abstract

Solute Carrier Family 19 Member 2 (<i>SLC19A2</i>) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. <i>SLC19A2</i> homozygous mutations have been described as a cause of thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive syndrome characterized by megaloblastic anemia, diabetes, and sensorineural deafness. Here we describe a loss-of-function <i>SLC19A2</i> mutation (c.A1063C: p.Lys355Gln) in a family with early-onset diabetes and mild TRMA traits transmitted in an autosomal dominant fashion. We show that <i>SLC19A2</i>-deficient β-cells are characterized by impaired thiamine uptake, which is not rescued by overexpression of the p.Lys355Gln mutant protein. We further demonstrate that <i>SLC19A2</i> deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link <i>SLC19A2</i> mutations to autosomal dominant diabetes and suggest a role of <i>SLC19A2</i> in β-cell function and survival.