Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene.
Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene.
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DOI：
10.1002/humu.22093
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发表时间：
2012-07
期刊：
影响因子：
3.9
通讯作者：
Lai, Kent
中科院分区：
文献类型：
--
作者：
Tang, Manshu;Facchiano, Angelo;Rachamadugu, Rakesh;Calderon, Fernanda;Mao, Rong;Milanesi, Luciano;Marabotti, Anna;Lai, Kent
Galactose-1-phosphate uridylyltransferase (GALT) catalyses the conversion of galactose-1-phosphate to UDP-galactose, a key step in the galactose metabolism. Deficiency of GALT activity in humans caused by deleterious variations in the GALT gene can cause a potentially lethal disease called Classic Galactosemia. In this study, we selected 14 novel nucleotide sequence changes in the GALT genes found in galactosemic patients for expression analysis and molecular modeling. Several variants showed decreased levels of expression and decreased abundance in the soluble fraction of the Escherichia coli cell extracts, suggesting altered stability and solubility. Only six variant GALT enzymes had detectable enzymatic activities. Kinetic studies showed that their Vmax decreased significantly. To further characterize the variants at molecular level, we performed static and dynamic molecular modeling studies. Effects of variations on local and/or global structural features of the enzyme were anticipated for the majority of variants. In-depth studies with molecular dynamic simulations on selected variants predicted the alteration of the protein structure even when static models apparently did not highlight any perturbation. Overall, these studies offered new insights on the molecular properties of GALT enzyme, with the aim of correlating them with the clinical outcome.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
56.9
作者：
ISSELBACHER, KJ;ANDERSON, EP;KALCKAR, HM
通讯作者：
KALCKAR, HM
影响因子：
3.6
作者：
GITZELMANN, R
通讯作者：
GITZELMANN, R
影响因子：
3.9
作者：
LELOIR, LF
通讯作者：
LELOIR, LF
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk