University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
Department Pediatrics, Centre for Child and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
EMBO Mol Med. 2021 Sep 7;13(9):e14332. doi: 10.15252/emmm.202114332. Epub 2021 Sep 1.
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.
先天性糖基化障碍是一组遗传和表型异质性的疾病，影响蛋白质的共翻译和翻译后修饰。使用外显子组测序，我们在一名表现为全面发育迟缓、轻度粗糙面容和生长不良的患者中检测到 GFUS（NM_003313.4）c.[632G>A];[659C>T]（p.[Gly211Glu];[Ser220Leu]）的双等位基因突变。GFUS 编码 GDP-L-岩藻糖合酶，是 GDP-L-岩藻糖从头合成的末端酶，是 N-和 O-聚糖岩藻糖基化所必需的。我们发现患者血清、白细胞、血小板和成纤维细胞中的 GFUS 蛋白减少和 GDP-L-岩藻糖水平降低，导致糖蛋白普遍低岩藻糖基化。用野生型 GFUS cDNA 补体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的蛋白质岩藻糖基化正常化。在 19 个月的随访中，观察到生长有中度改善，以及认知能力的明显改善，如 Kaufmann ABC 和 Nijmegen 儿科 CDG 评分量表所测量的。总之，GFUS-CDG 是一种新的糖基化障碍，口服 L-岩藻糖补充剂有前景。
