Novel GALT variations and mutation spectrum in the Korean population with decreased galactose-1-phosphate uridyltransferase activity

Abstract

Background: Classic galactosemia (OMIM #230400) is an autosomal recessive metabolic disorder caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT, EC2.7.7.12) protein due to mutations in the GALT gene. The aim of this study was to provide a comprehensive and updated mutation spectrum of GALT in a Korean population.

Methods: Thirteen unrelated patients screened positive for galactosemia in a newborn screening program were included in this study. They showed a reduced GALT enzyme activity in red blood cells. Direct sequencing of the GALT gene and in silico analyses were done to evaluate the impact of novel variations upon GALT enzyme activity. We also reviewed previous reports for GALT mutations in Koreans.

Results: We identified six novel likely pathogenic variations including three missense (p.Ala101Asp, p.Tyr165His, and p.Pro257Thr), one small deletion/insertion [c.826_827delinsAA (p.Ala276Asn)], one frameshift (p.Asn96Serfs*5), and one splicing (c.378-1G > C) likely pathogenic variations. The most frequent variation was the Duarte variant (c.940A > G, 35.3%), followed by c.507G > C (p.Gln169His, 9.6%), among 34 Korean patients. Other mutations were widely scattered. None of the eight common mutations used for targeted mutation analysis in Western countries including p.Gln188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, c.253-2A > G, and a 5 kb deletion, had been found in Koreans until this study.

Conclusions: Considering the mutation spectrum in Koreans, direct sequence analysis of entire GALT exons is recommended for accurate diagnosis. The mutations responsible for GALT deficiency in the Korean population were clearly different from those of other populations.

Figure 1

GALT enzyme activities among different categories of GALT biochemical phenotypes in 34 Korean patients. The bars in the boxes represent the median values, and the areas above and below the bars in the boxes represent the upper and lower quartiles, respectively. The lines extending below and above the boxes represent the lowest and highest values, respectively, and the circles represent individual data. P value was calculated by the comparison among five different groups of patients with GALT biochemical phenotypes by the Kruskal-Wallis test with post-hoc analysis (D, Duarte variant; G, mutant allele for galactosemia including novel likely pathogenic variant; N, normal allele). It is of note that although there were differences in GALT activity between the G/G and D/G patient groups, the GALT enzyme activities of individual patients were varied with overlapping distributions.