Wang Jin, Xiao Qi-Zhi, Chen You-Ming, Yi Sheng, Liu Dun, Liu Yan-Hui, Zhang Cui-Mei, Wei Xiao-Feng, Zhou Yu-Qiu, Zhong Xing-Ming, Zhao Cun-You, Xiong Fu, Wei Xiang-Cai, Xu Xiang-Min
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
Department of Birth Health and Heredity, Zhuhai Women and Children Care Hospital, Zhuhai, Guangdong, China.
Blood Cells Mol Dis. 2014 Dec;53(4):241-5. doi: 10.1016/j.bcmd.2014.06.001. Epub 2014 Jun 21.
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.
葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症是一种X连锁不完全显性的酶缺乏症，由G6PD基因突变引起。G6PD突变的女性杂合子表现出酶活性丧失的差异，但这种表型变异的原因尚不清楚。我们测定了71名G6PD缺乏的女性杂合子和68名具有相同错义突变（G6PD广州型c.1376G>T或开平型c.1388G>A）的G6PD非缺乏对照的DNA甲基化和X染色体失活模式，以将决定因素与可变表型相关联。G6PD启动子内特定的CpG甲基化在G6PD缺乏的杂合子中显著高于对照组。在杂合子中确定了G6PD野生型等位基因的优先X染色体失活。在缺乏的杂合子组中，优先X染色体失活的发生率为86.2%，在非缺乏的杂合子组中为31.7%。在杂合的G6PD广州型（r=-0.657，p<0.001）或开平型（r=-0.668，p<0.001）中，野生型等位基因的X染色体失活率与G6PD/6-磷酸葡萄糖酸脱氢酶（6PGD）比率之间观察到显著的负相关。多变量逻辑回归表明，G6PD启动子中特定CpG位点发生高甲基化且野生型等位基因优先X染色体失活的杂合子有酶缺乏的风险。
