PDF(Pubmed)
Abstract：
BACKGROUND: Congenital disorders of glycosylation (CDG) are a type of inborn error of metabolism (IEM) resulting from defects in glycan synthesis or failed attachment of glycans to proteins or lipids. One rare type of CDG is caused by homozygous or compound heterozygous loss-of-function variants in mannosidase alpha class 2B member 2 (MAN2B2). To date, only two cases of MAN2B2-CDG have been reported worldwide.
METHODS: Trio whole-exome sequencing (Trio-WES) was conducted to screen for candidate variants. N-glycan profiles were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MAN2B2 expression was evaluated by western blotting. MX dynamin like GTPase 1 (MX1) function was estimated via Thogoto virus (THOV) minireplicon assay.
RESULTS: Trio-WES identified compound heterozygous MAN2B2 (hg19, NM_015274.1) variants (c.384G>T; c.926T>A) in a CDG patient. This patient exhibited metabolic abnormalities, symptoms of digestive tract dysfunction, infection, dehydration, and seizures. Novel immune dysregulation characterized by abnormal lymphocytes and immunoglobulin was observed. The MAN2B2 protein level was not affected, while LC-MS/MS showed obvious disruption of N-glycans and N-linked glycoproteins.
CONCLUSIONS: We described a CDG patient with novel phenotypes and disruptive N-glycan profiling caused by compound heterozygous MAN2B2 variants (c.384G>T; c.926T>A). Our findings broadened both the genetic and clinical spectra of CDG.
METHODS: Trio whole-exome sequencing (Trio-WES) was conducted to screen for candidate variants. N-glycan profiles were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MAN2B2 expression was evaluated by western blotting. MX dynamin like GTPase 1 (MX1) function was estimated via Thogoto virus (THOV) minireplicon assay.
RESULTS: Trio-WES identified compound heterozygous MAN2B2 (hg19, NM_015274.1) variants (c.384G>T; c.926T>A) in a CDG patient. This patient exhibited metabolic abnormalities, symptoms of digestive tract dysfunction, infection, dehydration, and seizures. Novel immune dysregulation characterized by abnormal lymphocytes and immunoglobulin was observed. The MAN2B2 protein level was not affected, while LC-MS/MS showed obvious disruption of N-glycans and N-linked glycoproteins.
CONCLUSIONS: We described a CDG patient with novel phenotypes and disruptive N-glycan profiling caused by compound heterozygous MAN2B2 variants (c.384G>T; c.926T>A). Our findings broadened both the genetic and clinical spectra of CDG.
摘要：
背景：先天性糖基化障碍（CDG）是一种先天性代谢错误（IEM），由聚糖合成缺陷或聚糖与蛋白质或脂质的连接失败引起。一种罕见类型的CDG是由甘露糖苷酶α2B类成员2（MAN2B2）中的纯合或复合杂合功能丧失变体引起的。迄今为止,全球仅报道了2例MAN2B2-CDG.
方法：进行Trio全外显子组测序（Trio-WES）以筛选候选变体。通过液相色谱-串联质谱法(LC-MS/MS)测量N-聚糖谱。通过蛋白质印迹评价MAN2B2表达。通过Thogoto病毒（THOV）小复制子测定法估计MX动态蛋白样GTP酶1（MX1）功能。
结果:Trio-WES在CDG患者中鉴定了复合杂合MAN2B2(hg19,NM_015274.1)变体(c.384G>T;c.926T>A)。这个病人表现出代谢异常,消化道功能障碍的症状，感染,脱水,和癫痫发作。观察到以异常淋巴细胞和免疫球蛋白为特征的新型免疫失调。MAN2B2蛋白水平没有受到影响，而LC-MS/MS显示N-聚糖和N-连接糖蛋白的明显破坏。
结论：我们描述了一例CDG患者，其具有新的表型和由复合杂合MAN2B2变体引起的破坏性N-聚糖谱（c.384G>T;c.926T>A）。我们的发现扩大了CDG的遗传和临床谱。
方法：进行Trio全外显子组测序（Trio-WES）以筛选候选变体。通过液相色谱-串联质谱法(LC-MS/MS)测量N-聚糖谱。通过蛋白质印迹评价MAN2B2表达。通过Thogoto病毒（THOV）小复制子测定法估计MX动态蛋白样GTP酶1（MX1）功能。
结果:Trio-WES在CDG患者中鉴定了复合杂合MAN2B2(hg19,NM_015274.1)变体(c.384G>T;c.926T>A)。这个病人表现出代谢异常,消化道功能障碍的症状，感染,脱水,和癫痫发作。观察到以异常淋巴细胞和免疫球蛋白为特征的新型免疫失调。MAN2B2蛋白水平没有受到影响，而LC-MS/MS显示N-聚糖和N-连接糖蛋白的明显破坏。
结论：我们描述了一例CDG患者，其具有新的表型和由复合杂合MAN2B2变体引起的破坏性N-聚糖谱（c.384G>T;c.926T>A）。我们的发现扩大了CDG的遗传和临床谱。
