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

Abstract

Solute Carrier Family 19 Member 2 (SLC19A2) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. SLC19A2 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 SLC19A2 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 SLC19A2-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 SLC19A2 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link SLC19A2 mutations to autosomal dominant diabetes and suggest a role of SLC19A2 in β-cell function and survival.

The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2

“…Consistent with loss-of-function, confocal microscopy revealed that the SLC19A2 variants largely failed to traffic to the plasma membrane. Instead, intracellular puncta were observed for all three variants, suggestive of impaired transporter trafficking or recycling, a pattern that has been observed previously for mutations in SLC19A2 ( 26 , 27 ).…”

Loss of Mir146b with aging contributes to inflammation and mitochondrial dysfunction in thioglycollate-elicited peritoneal macrophages

“…Although genes upregulated in Mir146b- deficient macrophages are of interest as this pattern may indicate that Mir146b directly targets this/these gene(s) through canonical or non-canonical miRNA seed binding, we wanted to examine gene expression in a more global and unbiased manner so as to capture any significant changes in expression that may be related to mitochondrial dysfunction. We found several genes significantly downregulated in Mir146b cKO TGEMs, which have critical roles in both mitochondrial morphology and respiration ( Sdhd , Crtc2 , Pnpt1 , Gdf15 , Mrps28 , Mterf3 , Med30 Rnaseh1 , Slc19a2 , and Gtpbp10 ) ( Gottlieb and Tomlinson, 2005 ; Linke et al, 2017 ; Shimada et al, 2018 ; Liu et al, 2019 ; Sylvester et al, 2004 ; Taylor and Turnbull, 2007 ; Krebs et al, 2011 ; Lima et al, 2016 ; Jungtrakoon et al, 2019 ; Lavdovskaia et al, 2018 ; Figure 4A ). These findings suggest that macrophage Mir146b deficiency affects genes in the macrophage transcriptome that broadly regulate mitochondrial function and metabolism, leading to mitochondrial dysfunction and reduced metabolic capacity, similar to what is seen with aging ( Xia et al, 2016 ; van Beek et al, 2019 ; Pence and Yarbro, 2018 ).…”

Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries

“…MODY can occur at different ages from childhood to early adulthood, while presenting with variable clinical features both at diagnosis and later in life [1,6]. Beyond MODY, the wide clinical spectrum of MD is substantially explained by genetic heterogeneity with various types of genetic defects in more than 30 genes, depending on the consensus of established causal genes, including some involved in rarer forms of early infancy-onset diabetes [1,6,7]. Importantly, a formal genetic diagnosis is the only way to recognize MD from common type 2 diabetes.…”