Department of Medicine, Harvard Medical School, Boston, MA.
Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA.
Diabetes. 2019 May;68(5):1084-1093. doi: 10.2337/db17-0821. Epub 2019 Mar 4.
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.
溶质载体家族 19 成员 2()编码硫胺素转运蛋白 1(THTR1)，它促进硫胺素穿过细胞膜的运输。纯合突变已被描述为硫胺素反应性巨幼细胞性贫血(TRMA)的原因，这是一种常染色体隐性遗传综合征，其特征为巨幼细胞性贫血、糖尿病和感觉神经性耳聋。在这里，我们描述了一个家族中存在的功能丧失突变(c.A1063C：p.Lys355Gln)，该家族具有早发性糖尿病和轻度 TRMA 特征，以常染色体显性方式遗传。我们表明-缺陷的β细胞的特征是摄取硫胺素受损，而过表达 p.Lys355Gln 突变蛋白并不能挽救这种情况。我们进一步证明，缺陷导致胰岛素分泌受损，同时伴有线粒体功能障碍、对氧化应激的保护丧失和细胞周期停滞。这些发现将突变与常染色体显性糖尿病联系起来，并表明在β细胞功能和存活中起作用。
