Wopereis Suzan, Morava Eva, Grünewald Stephanie, Mills Philippa B, Winchester Bryan G, Clayton Peter, Coucke Paul, Huijben Karin M L C, Wevers Ron A
Radboud University Nijmegen Medical Center, Laboratory of Pediatrics and Neurology, Institute of Neurology, Reinier Postlaan 4, 6525 GC Nijmegen, The Netherlands.
Biochim Biophys Acta. 2005 Jun 30;1741(1-2):156-64. doi: 10.1016/j.bbadis.2004.11.009. Epub 2004 Dec 9.
Based on our preliminary observation of abnormal glycosylation in a cutis laxa patient, nine cutis laxa patients were analyzed for congenital defects of glycosylation (CDG). Isoelectric focusing of plasma transferrin and apolipoproteinC-III showed that three out of nine patients had a defect in the biosynthesis of N-glycans and core 1 mucin type O-glycans, respectively. Mass spectrometric N-glycan analyses revealed a relative increase of glycans lacking sialic acid and glycans lacking sialic acid and galactose residues. Mutation analysis of the fibulin-5 gene (FBLN5), which has been reported in cases of autosomal recessive cutis laxa, revealed no mutations in the patients' DNA. Evidence is presented that extracellular matrix (ECM) proteins of skin are likely to be highly glycosylated with N- and/or mucin type O-glycans by using algorithms for predicting glycosylation. The conclusions in this study were that the clinical phenotype of autosomal recessive cutis laxa seen in three patients is not caused by mutations in the FBLN5 gene. Our findings define a novel form of CDG with cutis laxa and neurological involvement due to a defect in the sialylation and/or galactosylation of N- and O-glycans. Improper glycosylation of ECM proteins of skin may form the pathophysiological basis for the cutis laxa phenotype.
基于我们对一名皮肤松弛症患者糖基化异常的初步观察，对9名皮肤松弛症患者进行了先天性糖基化缺陷（CDG）分析。血浆转铁蛋白和载脂蛋白C-III的等电聚焦显示，9名患者中有3名分别在N-聚糖和核心1粘蛋白型O-聚糖的生物合成方面存在缺陷。质谱N-聚糖分析显示，缺乏唾液酸的聚糖以及缺乏唾液酸和半乳糖残基的聚糖相对增加。对常染色体隐性遗传性皮肤松弛症病例中报道的腓骨蛋白-5基因（FBLN5）进行突变分析，结果显示患者DNA中未发现突变。通过使用预测糖基化的算法，有证据表明皮肤的细胞外基质（ECM）蛋白可能高度糖基化有N-和/或粘蛋白型O-聚糖。本研究的结论是，3名患者中所见的常染色体隐性遗传性皮肤松弛症的临床表型并非由FBLN5基因突变引起。我们的研究结果定义了一种新型的CDG，其伴有皮肤松弛症和神经受累，原因是N-聚糖和O-聚糖的唾液酸化和/或半乳糖基化存在缺陷。皮肤ECM蛋白的糖基化不当可能构成皮肤松弛症表型的病理生理基础。
