Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement.
Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement.
复制标题
MAN2A2 中的纯合截短变异会导致一种新型先天性糖基化疾病，并累及神经系统。
DOI：
10.1136/jmg-2022-108821
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发表时间：
2023
影响因子：
4
通讯作者：
Freeze,HudsonH
中科院分区：
文献类型：
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作者：
Mahajan,Sonal;Ng,BobbyGeorge;AlAbdi,Lama;Earnest,PaulDanielJames;Sosicka,Paulina;Patel,Nisha;Helaby,Rana;Abdulwahab,Firdous;He,Miao;Alkuraya,FowzanS;Freeze,HudsonH
背景参与N-聚糖加工的高尔基体酶对大脑发育至关重要，许多酶的缺陷被定义为先天性糖基化障碍（CDG）。参与的高尔基甘露糖苷酶，MAN 2A 2尚未确定以前引起糖基化deficiency.MethodsExome测序的受影响的个人进行了桑格测序的theMAN 2A 2转录确认的变体。在患者来源的淋巴母细胞中分析N-聚糖，以确定变体的功能效应。一个基于细胞的互补试验的目的是评估使用MAN 2A 1/MAN 2A 2双敲除HEK 293细胞株的致病性的确定的变体。ResultsWe确定了一个多重的血缘家庭与纯合截断变异p.Val1101Ter在MAN 2A 2。携带相同截短变体的两个受影响兄弟的淋巴母细胞显示复合N-聚糖减少和杂合N-聚糖积累。在开发的互补试验中测试这种变体，我们看到完全缺乏复杂的N-glycans.ConclusionOur研究结果表明，致病性变异MAN 2A 2导致一种新的常染色体隐性CDG与神经系统的参与和面部畸形。在这里，我们还提出了一种基于细胞的互补试验的发展，以评估MAN 2A 2变异体的致病性，这也可以扩展到MAN 2A 1变异体用于未来的诊断。
BackgroundEnzymes of the Golgi implicated in N-glycan processing are critical for brain development, and defects in many are defined as congenital disorders of glycosylation (CDG). Involvement of the Golgi mannosidase, MAN2A2 has not been identified previously as causing glycosylation defects.MethodsExome sequencing of affected individuals was performed with Sanger sequencing of theMAN2A2transcript to confirm the variant. N-glycans were analysed in patient-derived lymphoblasts to determine the functional effects of the variant. A cell-based complementation assay was designed to assess the pathogenicity of identified variants using MAN2A1/MAN2A2 double knock out HEK293 cell lines.ResultsWe identified a multiplex consanguineous family with a homozygous truncating variant p.Val1101Ter in MAN2A2. Lymphoblasts from two affected brothers carrying the same truncating variant showed decreases in complex N-glycans and accumulation of hybrid N-glycans. On testing of this variant in the developed complementation assay, we see the complete lack of complex N-glycans.ConclusionOur findings show that pathogenic variants in MAN2A2 cause a novel autosomal recessive CDG with neurological involvement and facial dysmorphism. Here, we also present the development of a cell-based complementation assay to assess the pathogenicity of MAN2A2 variants, which can also be extended to MAN2A1 variants for future diagnosis.