Loss-of-Function Mutations of CHST14 in a New Type of Ehlers-Danlos Syndrome
Loss-of-Function Mutations of CHST14 in a New Type of Ehlers-Danlos Syndrome
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DOI：
10.1002/humu.21300
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发表时间：
2010-08-01
期刊：
影响因子：
3.9
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Miyake, Noriko;Kosho, Tomoki;Matsumoto, Naomichi
ehers - danlos综合征（EDS）是一种异质性结缔组织疾病，涉及皮肤和关节松弛和组织脆弱。研究了一种与脊柱后凸型相似但没有赖基羟化酶缺乏症的新型EDS。我们在两个家族性病例中发现了纯合子CHST14（碳水化合物硫转移酶14）突变，在四个散发性病例中发现了复合杂合突变。CHST14编码皮肤聚糖4- o -硫转移酶1 (D4ST1)，将活性硫酸盐从3'-磷酸腺苷5'-磷酸硫酸转移到皮肤聚糖（DS） n -乙酰- d -半乳糖胺（GalNAc）残基的第4位。突变体的转染实验和患者成纤维细胞裂解物的酶分析显示D4ST1活性丧失。CHST14突变改变了患者成纤维细胞中的糖胺聚糖（GAG）成分。有趣的是，在患者的成纤维细胞中，胶原原纤维组装的关键调节因子decorin蛋白多糖的DS完全丢失，并被硫酸软骨素（CS）所取代，导致GAG链的柔韧性下降。由于CHST14突变导致的decorin DS蛋白聚糖的缺失可能会阻碍胶原束的形成或胶原束的维持，而在患者的真皮组织中观察到的胶原原纤维的大小和形状不变。这些发现提示了decorin DS在细胞外基质中的重要作用和EDS的一种新的病理机制。[j] .中国生物医学工程学报，2010。(C) 2010 Wiley-Liss, Inc。
Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 4 of the N-acetyl-D-galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS. Hum Mutat 31: 966-974, 2010. (C) 2010 Wiley-Liss, Inc.