title: DNA hypermethylation and X chromosome inactivation are major determinants of phenotypic variation in women heterozygous for G6PD mutations.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked incompletely dominant enzyme deficiency that results from G6PD gene mutations. Women heterozygous for G6PD mutations exhibit variation in the loss of enzyme activity but the cause of this phenotypic variation is unclear. We determined DNA methylation and X-inactivation patterns in 71 G6PD-deficient female heterozygotes and 68 G6PD non-deficient controls with the same missense mutations (G6PD Canton c.1376G>T or Kaiping c.1388G>A) to correlate determinants with variable phenotypes. Specific CpG methylations within the G6PD promoter were significantly higher in G6PD-deficient heterozygotes than in controls. Preferential X-inactivation of the G6PD wild-type allele was determined in heterozygotes. The incidence of preferential X-inactivation was 86.2% in the deficient heterozygote group and 31.7% in the non-deficient heterozygote group. A significant negative correlation was observed between X-inactivation ratios of the wild-type allele and G6PD/6-phosphogluconate dehydrogenase (6PGD) ratios in heterozygous G6PD Canton (r=-0.657, p<0.001) or Kaiping (r=-0.668, p<0.001). Multivariate logistic regression indicated that heterozygotes with hypermethylation of specific CpG sites in the G6PD promoter and preferential X-inactivation of the wild-type allele were at risk of enzyme deficiency.
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors: Jin
authors: J
authors: Wang
authors: Department of Birth Health and Heredity, Zhuhai Women and Children Care Hospital, Zhuhai, Guangdong, China.
authors: Qi-Zhi
authors: QZ
authors: Xiao
authors: Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.
authors: You-Ming
authors: YM
authors: Chen
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors: Sheng
authors: S
authors: Yi
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors: Dun
authors: D
authors: Liu
authors: Prenatal Diagnosis Center, Dongguan Maternal and Child Health Hospital, Dongguan, Guangdong, China.
authors: Yan-Hui
authors: YH
authors: Liu
authors: Department of Child Health, Boai Hospital of Zhongshan, Zhongshan, Guangdong, China.
authors: Cui-Mei
authors: CM
authors: Zhang
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors: Xiao-Feng
authors: XF
authors: Wei
authors: Department of Birth Health and Heredity, Zhuhai Women and Children Care Hospital, Zhuhai, Guangdong, China.
authors: Yu-Qiu
authors: YQ
authors: Zhou
authors: Department of Reproductive Immunology and Endocrinology, Family Planning Research Institute of Guangdong, Guangzhou, Guangdong, China.
authors: Xing-Ming
authors: XM
authors: Zhong
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors: Cun-You
authors: CY
authors: Zhao
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors: Fu
authors: F
authors: Xiong
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Department of Reproductive Immunology and Endocrinology, Family Planning Research Institute of Guangdong, Guangzhou, Guangdong, China.
authors: Xiang-Cai
authors: XC
authors: Wei
authors: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: gzxuxm@pub.guangzhou.gd.cn.
authors: Xiang-Min
authors: XM
authors: Xu
mesh_terms: D000328:Adult; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D016015:Logistic Models; D058977:Molecular Sequence Annotation; D020125:Mutation, Missense; D010641:Phenotype; D010734:Phosphogluconate Dehydrogenase / Q000235:genetics; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D049951:X Chromosome Inactivation
chemical_list: D010734:Phosphogluconate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase
keywords: G6PD; Methylation; Phenotypic variation; Women heterozygous; X chromosome inactivation