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Abnormal glycosylation in Joubert syndrome type 10

机译：Joubert综合征10型糖基化异常

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Background The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and manifested features of Joubert syndrome. Methods We integrated exome sequencing, MALDI-TOF mass spectrometry analyses of plasma and cultured dermal fibroblasts glycomes, and full clinical evaluation of the proband. Analyses of cilia formation and lectin staining were performed by immunofluorescence. Measurement of cellular nucleotide sugar levels was performed with high-performance anion-exchange chromatography with pulsed amperometric detection. Statistical analyses utilized the Student’s and Fisher’s exact t tests. Results Glycome analyses of plasma and cultured dermal fibroblasts identified abnormal N - and O -linked glycosylation profiles. These findings replicated in two unrelated males with OFD1 mutations. Cultured fibroblasts from affected individuals had a defect in ciliogenesis. The proband’s fibroblasts also had an abnormally elevated nuclear sialylation signature and increased total cellular levels of CMP-sialic acid. Ciliogenesis and each glycosylation anomaly were rescued by expression of wild-type OFD1 . Conclusions The rescue of ciliogenesis and glycosylation upon reintroduction of WT OFD1 suggests that both contribute to the pathogenesis of JBTS10.
机译：背景技术疾病发病机理的发现需要对可能会失调的多个稳态过程进行系统的不可知性筛选。我们在一个5岁的Joubert综合征10型男孩（JBTS10）的评估和诊断中说明了这一原理。他携带OFD1突变p.Gln886Lysfs * 2（NM_003611.2：c.2656del），并表现出Joubert综合征的特征。方法我们整合了外显子组测序，血浆和培养的真皮成纤维细胞糖原的MALDI-TOF质谱分析，并对先证者进行了全面的临床评估。通过免疫荧光进行纤毛形成和凝集素染色的分析。细胞核糖水平的测定是通过带有脉冲安培检测的高效阴离子交换色谱法进行的。统计分析利用了学生和费舍尔的精确t检验。结果血浆和培养的真皮成纤维细胞的糖液分析确定了异常的N-和O-连锁糖基化谱。这些发现在两名具有OFD1突变的无关男性中复制。来自受影响个体的培养成纤维细胞在睫毛发生中存在缺陷。先证者的成纤维细胞还具有异常的核唾液酸化信号升高和CMP-唾液酸总细胞水平升高。通过野生型OFD1的表达挽救了纤毛发生和每个糖基化异常。结论WT OFD1的重新导入可挽救纤毛发生和糖基化，这两者均有助于JBTS10的发病。

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