The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree.
The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree.
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DOI：
10.1093/function/zqab040
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Wright EM
中科院分区：
文献类型：
--
作者：
Lostao MP;Loo DD;Hernell O;Meeuwisse G;Martin MG;Wright EM
葡萄糖-半乳糖吸收不良（GGM）是由于肠道葡萄糖钠共转运体SGLT1 （SLC5A1）基因编码突变引起的。在这里，我们在瑞典北部Västerbotten县的一个具有GGM临床表型的大谱系患者中发现了罕见的变异Gln457Arg （Q457R）。采用生物物理和生化方法检测了Q457R突变对非洲爪蟾卵母细胞蛋白表达的功能影响。突变体无法转运SGLT1特异的糖类似物α-甲基- d -葡萄糖苷（αMDG）。Q457R SGLT1的合成量与野生型（WT）转运体相当。SGLT1电荷测量和冷冻断裂电镜显示突变蛋白被插入质膜。稳态和预稳态电生理实验表明，突变体结合糖的亲和力低于WT转运体。结合我们之前对Q457C和Q457E突变体的研究，我们确定了Q457R上的正电荷阻止了糖从外向内的构象转移到内向的构象。这与其他误义突变导致SGLT1转运到质膜缺陷的GGM病例相反。13名GGM患者现在被添加到可追溯到17世纪晚期的谱系中。Västerbotten县基因组中Q457R变异的频率为0.0067，高于瑞典一般人群的0.0015，高于欧洲一般人群的0.000067。这解释了瑞典这一地区的GGM病例数量高的原因。
Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.
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影响因子：
29.4
作者：
Thiagarajah JR;Kamin DS;Acra S;Goldsmith JD;Roland JT;Lencer WI;Muise AM;Goldenring JR;Avitzur Y;Martín MG;PediCODE Consortium
通讯作者：
PediCODE Consortium
DOI：
10.1016/s0925-4439(98)00109-4
发表时间：
1999-02-24
影响因子：
6.2
作者：
Lam, JT;Martín, MG;Wright, EM
通讯作者：
Wright, EM
影响因子：
3.7
作者：
Rentoft, Matilda;Svensson, Daniel;Johansson, Erik
通讯作者：
Johansson, Erik
影响因子：
5.5
作者：
Sala-Rabanal, Monica;Hirayama, Bruce A.;Wright, Ernest M.
通讯作者：
Wright, Ernest M.
影响因子：
4.5
作者：
BIRNIR, B;LOO, DDF;WRIGHT, EM
通讯作者：
WRIGHT, EM