Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co- and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM_003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220Leu]) in a patient presenting with global developmental delay, mild coarse facial features and faltering growth. GFUS encodes GDP-L-fucose synthase, the terminal enzyme in de novo synthesis of GDP-L-fucose, required for fucosylation of N- and O-glycans. We found reduced GFUS protein and decreased GDP-L-fucose levels leading to a general hypofucosylation determined in patient's glycoproteins in serum, leukocytes, thrombocytes and fibroblasts. Complementation of patient fibroblasts with wild-type GFUS cDNA restored fucosylation. Making use of the GDP-L-fucose salvage pathway, oral fucose supplementation normalized fucosylation of proteins within 4 weeks as measured in serum and leukocytes. During the follow-up of 19 months, a moderate improvement of growth was seen, as well as a clear improvement of cognitive skills as measured by the Kaufmann ABC and the Nijmegen Pediatric CDG Rating Scale. In conclusion, GFUS-CDG is a new glycosylation disorder for which oral L-fucose supplementation is promising.

中文翻译：

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一勺 L-岩藻糖——治疗新型糖基化障碍 GFUS-CDG 的有效方法

先天性糖基化障碍是影响蛋白质共翻译和翻译后修饰的遗传和表型异质性疾病家族。使用外显子组测序，我们在一名患有整体发育迟缓、轻度粗糙的患者中检测到GFUS (NM_003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220Leu]) 中的双等位基因变异面部特征和生长缓慢。GFUS编码 GDP-L-岩藻糖合酶，GDP-L-岩藻糖从头合成的末端酶，是 N- 和 O- 聚糖岩藻糖基化所需的。我们发现 GFUS 蛋白减少和 GDP-L-岩藻糖水平降低，导致患者血清、白细胞、血小板和成纤维细胞中的糖蛋白普遍低岩藻糖基化。用野生型GFUS cDNA 补充患者成纤维细胞可恢复岩藻糖基化。利用 GDP-L-岩藻糖补救途径，口服岩藻糖补充剂可在 4 周内使血清和白细胞中测量的蛋白质岩藻糖基化正常化。在 19 个月的随访中，生长情况出现了适度的改善，根据考夫曼 ABC 和奈梅亨儿科 CDG 评定量表衡量，认知技能也有明显改善。总之，GFUS-CDG 是一种新的糖基化疾病，口服 L-岩藻糖补充剂有望治疗该疾病。