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Hum Mutat
2019 Jul 01;407:983-995. doi: 10.1002/humu.23758.
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Functional and structural analysis of rare SLC2A2 variants associated with Fanconi-Bickel syndrome and metabolic traits.
Enogieru OJ
,
Ung PMU
,
Yee SW
,
Schlessinger A
,
Giacomini KM
.
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Deleterious variants in SLC2A2 cause Fanconi-Bickel Syndrome (FBS), a glycogen storage disorder, whereas less common variants in SLC2A2 associate with numerous metabolic diseases. Phenotypic heterogeneity in FBS has been observed, but its causes remain unknown. Our goal was to functionally characterize rare SLC2A2 variants found in FBS and metabolic disease-associated variants to understand the impact of these variants on GLUT2 activity and expression and establish genotype-phenotype correlations. Complementary RNA-injected Xenopus laevis oocytes were used to study mutant transporter activity and membrane expression. GLUT2 homology models were constructed for mutation analysis using GLUT1, GLUT3, and XylE as templates. Seventeen FBS variants were characterized. Only c.457_462delCTTATA (p.Leu153_Ile154del) exhibited residual glucose uptake. Functional characterization revealed that only half of the variants were expressed on the plasma membrane. Most less common variants (except c.593 C>A (p.Thr198Lys) and c.1087 G>T (p.Ala363Ser)) exhibited similar GLUT2 transport activity as the wild type. Structural analysis of GLUT2 revealed that variants affect substrate-binding, steric hindrance, or overall transporter structure. The mutant transporter that is associated with a milder FBS phenotype, p.Leu153_Ile154del, retained transport activity. These results improve our overall understanding of the underlying causes of FBS and impact of GLUT2 function on various clinical phenotypes ranging from rare to common disease.
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30950137
???displayArticle.pmcLink???PMC7137536 ???displayArticle.link???Hum Mutat ???displayArticle.grants???[+]
BWF ID 1012485 Burroughs Wellcome Fund, GM108911 National Institutes of Health, GM117163 National Institutes of Health, R25 GM56847 National Institutes of Health, GM108911 NIH HHS , GM117163 NIH HHS , R25 GM56847 NIH HHS , R01 GM108911 NIGMS NIH HHS , R01 GM117163 NIGMS NIH HHS , R25 GM056847 NIGMS NIH HHS
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