PDF(Pubmed)
Abstract：
Congenital glucose-galactose malabsorption is a rare autosomal recessive disorder caused by mutations in SLC5A1 encoding the apical sodium/glucose cotransporter SGLT1. We present clinical and molecular data from eleven affected individuals with congenital glucose-galactose malabsorption from four unrelated, consanguineous Turkish families. Early recognition and timely management by eliminating glucose and galactose from the diet are fundamental for affected individuals to survive and develop normally. We identified novel SLC5A1 missense variants, p.Gly43Arg and p.Ala92Val, which were linked to disease in two families. Stable expression in CaCo-2 cells showed that the p.Ala92Val variant did not reach the plasma membrane, but was retained in the endoplasmic reticulum. The p.Gly43Arg variant, however, displayed processing and plasma membrane localization comparable to wild-type SGLT1. Glycine-43 displays nearly invariant conservation in the relevant structural family of cotransporters and exchangers, and localizes to SGLT1 transmembrane domain TM0. p.Gly43Arg represents the first disease-associated variant in TM0; however, the role of TM0 in the SGLT1 function has not been established. In summary, we are expanding the mutational spectrum of this rare disorder.
摘要：
先天性葡萄糖-半乳糖吸收不良是一种罕见的常染色体隐性遗传疾病，由编码顶端钠/葡萄糖协同转运蛋白SGLT1的SLC5A1突变引起。我们提供了来自11名患有先天性葡萄糖-半乳糖吸收不良的受影响个体的临床和分子数据，有血缘关系的土耳其家庭.通过从饮食中消除葡萄糖和半乳糖的早期识别和及时管理是受影响个体正常生存和发育的基础。我们鉴定了新的SLC5A1错义变体，p.Gly43Arg和p.Ala92Val,这与两个家庭的疾病有关。在CaCo-2细胞中的稳定表达表明p.Ala92Val变体未到达质膜，但保留在内质网中。p.Gly43Arg变体,然而,显示处理和质膜定位与野生型SGLT1相当。甘氨酸-43在相关的共转运体和交换体结构家族中显示出几乎不变的保守性，并定位到SGLT1跨膜结构域TM0。p.Gly43Arg代表TM0中的第一个疾病相关变异；然而，TM0在SGLT1功能中的作用尚未建立。总之,我们正在扩大这种罕见疾病的突变范围。
