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

Solute Carrier Family 19 Member 2 () encodes thiamine transporter 1 (THTR1)， which facilitates thiamine transport across the cell membrane. 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 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 -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 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction， loss of protection against oxidative stress， and cell cycle arrest. These findings link mutations to autosomal dominant diabetes and suggest a role of in β-cell function and survival.