Ann Lab Med.  2017 Mar;37(2):108-116. 10.3343/alm.2017.37.2.108.

Genetic Profiles of Korean Patients With Glucose-6-Phosphate Dehydrogenase Deficiency

Affiliations
  • 1Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. miziro@catholic.ac.kr
  • 2Catholic Genetic Laboratory Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • 3Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea. chobinkr@catholic.ac.kr

Abstract

BACKGROUND
We describe the genetic profiles of Korean patients with glucose-6-phosphate dehydrogenase (G6PD) deficiencies and the effects of G6PD mutations on protein stability and enzyme activity on the basis of in silico analysis.
METHODS
In parallel with a genetic analysis, the pathogenicity of G6PD mutations detected in Korean patients was predicted in silico. The simulated effects of G6PD mutations were compared to the WHO classes based on G6PD enzyme activity. Four previously reported mutations and three newly diagnosed patients with missense mutations were estimated.
RESULTS
One novel mutation (p.Cys385Gly, labeled G6PD Kangnam) and two known mutations [p.Ile220Met (G6PD São Paulo) and p.Glu416Lys (G6PD Tokyo)] were identified in this study. G6PD mutations identified in Koreans were also found in Brazil (G6PD São Paulo), Poland (G6PD Seoul), United States of America (G6PD Riley), Mexico (G6PD Guadalajara), and Japan (G6PD Tokyo). Several mutations occurred at the same nucleotide, but resulted in different amino acid residue changes in different ethnic populations (p.Ile380 variant, G6PD Calvo Mackenna; p.Cys385 variants, Tomah, Madrid, Lynwood; p.Arg387 variant, Beverly Hills; p.Pro396 variant, Bari; and p.Pro396Ala in India). On the basis of the in silico analysis, Class I or II mutations were predicted to be highly deleterious, and the effects of one Class IV mutation were equivocal.
CONCLUSIONS
The genetic profiles of Korean individuals with G6PD mutations indicated that the same mutations may have arisen by independent mutational events, and were not derived from shared ancestral mutations. The in silico analysis provided insight into the role of G6PD mutations in enzyme function and stability.

Keyword

Glucose-6-phosphate dehydrogenase deficiency; Mutation; In silico analysis; Korean

MeSH Terms

Asian Continental Ancestry Group/*genetics
Child
Child, Preschool
DNA/chemical synthesis/genetics/metabolism
Exons
Glucosephosphate Dehydrogenase/chemistry/*genetics/metabolism
Glucosephosphate Dehydrogenase Deficiency/*genetics/pathology
Humans
Male
Mutation, Missense
Polymorphism, Genetic
Protein Structure, Tertiary
Republic of Korea
Sequence Analysis, DNA
DNA
Glucosephosphate Dehydrogenase

Figure

  • Fig. 1 Molecular visualization of the wild-type (WT) (left) and variant (right) amino acid using the FoldX function of SNPeffect 4.0. If the mutation destabilizes the structure, ddG (ΔΔG) is increased, whereas stabilizing mutations decrease ddG. Since the FoldX error margin is approximately 0.5 kcal/mol, changes in this range are considered insignificant. (A, B) The mutation from Ile (red in A) to Met (red in B) at position 220 resulted in a ddG of -0.38 kcal/mol. This implies that the mutation had no effect on protein stability. (C, D) The mutation from Gly (red in C) to Ser (red in D) at position 306 resulted in a ddG of 2.81 kcal/mol. This implies that the mutation reduced protein stability. (E, F) The mutation from Ile (red in E) to Thr (red in F) at position 380 resulted in a ddG of 0.56 kcal/mol. This implies that the mutation slightly reduced protein stability. (G, H) The mutation from Cys (red in G) to Gly (red in H) at position 385 resulted in a ddG of 0.65 kcal/mol. This implies that the mutation slightly reduced protein stability. (I, J) The mutation from Arg (red in I) to Cys (red in J) at position 387 resulted in a ddG of 2.18 kcal/mol. This implies that the mutation reduced protein stability. (K, L) The mutation from Pro (red in K) to Arg (red in L) at position 396 resulted in a ddG of 3.19 kcal/mol. This implies that the mutation reduced protein stability. (M and N) The mutation from Glu (red in M) to Lys (red in N) at position 416 resulted in a ddG of -0.86 kcal/mol. This implies that the mutation slightly enhanced protein stability.


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