TAILIEUCHUNG - Báo cáo khoa học: Functional analysis of mutations in UDP-galactose-4epimerase (GALE) associated with galactosemia in Korean patients using mammalian GALE-null cells

Galactosemia is caused by defects in the galactose metabolic pathway, which consists of three enzymes, including UDP-galactose-4-epimerase (GALE). We previously reported nine mutations in Korean patients with epimerase-deficiency galactosemia. In order to determine the functional consequences of these mutations, we expressed wild-type and mutant GALE proteins in 293T cells. | ễFEBS Journal Functional analysis of mutations in UDP-galactose-4-epimerase GALE associated with galactosemia in Korean patients using mammalian GALE-null cells You-Lim Bang1 z Trang T. T. Nguyen1 z Tram T. B. Trinh1 z Yun J. Kim1 Junghan Song2 and Young-Han Song1 1 Ilsong Institute of Life Science Hallym University Anyang Korea 2 Department of Laboratory Medicine SeoulNationalUniversity Bundang Hospital Gyeonggi-do Korea Keywords galactosemia mutation protein aggregation UDP-galactose-4-epimerase unstable protein Correspondence . Song Ilsong Institute of Life Science Hallym University 1605-4 Gwanyang-dong Dongan-gu Anyang Gyeonggi-do 431 060 Korea Fax 82 31 388 3427 Tel 82 31 380 1897 E-mail ysong@ These authors contributed equally to this work Received 15 December 2008 revised 19 January 2009 accepted 21 January 2009 doi Galactosemia is caused by defects in the galactose metabolic pathway which consists of three enzymes including UDP-galactose-4-epimerase GALE . We previously reported nine mutations in Korean patients with epimerase-deficiency galactosemia. In order to determine the functional consequences of these mutations we expressed wild-type and mutant GAlE proteins in 293T cells. GALEe165K and GALEW336X proteins were unstable had reduced half-life formed aggregates and were partly degraded by the proteasome complex. When expressed in GALE-null IdlD cells GAlEe165K GALER239W GALEG302d and GALEW336X had no detectable enzyme activity although substantial amounts of protein were detected in western blots. The relative activities of other mutants were lower than that of wild-type. In addition unlike wild-type GALER239W and GALEG302D were not able to rescue galactose-sensitive cell proliferation when stably expressed in IdlD cells. The four inactive mutant proteins did not show defects in dimerization or affect the activity of other mutant alleles identified in patients. Our observations show that altered protein

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