Department of Medical Genetics, Erciyes University, Talas, 38039 Kayseri, Turkey.
Am J Hum Genet. 2009 Dec;85(6):873-82. doi: 10.1016/j.ajhg.2009.11.010.
Adducted thumb-clubfoot syndrome is an autosomal-recessive disorder characterized by typical facial appearance, wasted build, thin and translucent skin, congenital contractures of thumbs and feet, joint instability, facial clefting, and coagulopathy, as well as heart, kidney, or intestinal defects. We elucidated the molecular basis of the disease by using a SNP array-based genome-wide linkage approach that identified distinct homozygous nonsense and missense mutations in CHST14 in each of four consanguineous families with this disease. The CHST14 gene encodes N-acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1), which catalyzes 4-O sulfation of N-acetylgalactosamine in the repeating iduronic acid-alpha1,3-N-acetylgalactosamine disaccharide sequence to form dermatan sulfate. Mass spectrometry of glycosaminoglycans from a patient's fibroblasts revealed absence of dermatan sulfate and excess of chondroitin sulfate, showing that 4-O sulfation by CHST14 is essential for dermatan sulfate formation in vivo. Our results indicate that adducted thumb-clubfoot syndrome is a disorder resulting from a defect specific to dermatan sulfate biosynthesis and emphasize roles for dermatan sulfate in human development and extracellular-matrix maintenance.
内收拇指并趾综合征是一种常染色体隐性遗传病，其特征为典型的面部特征、消瘦体型、皮肤菲薄且半透明、拇指和足部先天性挛缩、关节不稳定、面部裂、凝血功能障碍以及心脏、肾脏或肠道缺陷。我们通过 SNP 芯片全基因组连锁分析方法阐明了该疾病的分子基础，在四个患有该病的近亲家庭中，每个家庭均发现 CHST14 基因存在明显的纯合无义突变和错义突变。CHST14 基因编码 N-乙酰半乳糖胺 4-O-硫酸转移酶 1（D4ST1），该酶可催化重复的艾杜糖醛酸-α1,3-N-乙酰半乳糖胺二糖序列中 N-乙酰半乳糖胺的 4-O 硫酸化，形成硫酸皮肤素。患者成纤维细胞的糖胺聚糖的质谱分析显示硫酸皮肤素缺失和硫酸软骨素过量，表明 CHST14 的 4-O 硫酸化对体内硫酸皮肤素的形成是必不可少的。我们的研究结果表明，内收拇指并趾综合征是一种由特定于硫酸皮肤素生物合成的缺陷引起的疾病，并强调了硫酸皮肤素在人类发育和细胞外基质维持中的作用。
