Mäkitie Outi, Savarirayan Ravi, Bonafé Luisa, Robertson Stephen, Susic Miki, Superti-Furga Andrea, Cole William G
Center for the Study of Heritable Connective Tissue Diseases, Research Institute, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Am J Med Genet A. 2003 Oct 15;122A(3):187-92. doi: 10.1002/ajmg.a.20282.
Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene result in a family of skeletal dysplasias, which comprise lethal (achondrogenesis type 1B and atelosteogenesis type 2) and non-lethal conditions (diastrophic dysplasia and recessive multiple epiphyseal dysplasia (rMED)). The most frequent mutation is R279W, which in a homozygous state results in rMED with bilateral clubfoot, MED, and "double layered" patella. We describe three patients with rMED caused by a previously unreported homozygous mutation in the DTDST gene. The three patients (from two families) were born to healthy, non-consanguineous parents. All developed signs of hip dysplasia in early childhood and two had episodes of recurrent patella dislocation. Two underwent bilateral total hip replacements at ages 13 and 14 years. The feet, external ears, and palate were normal. Stature was normal in all cases. Radiographs showed dysplastic femoral heads, mild generalized epiphyseal dysplasia, abnormal patella ossification, and normal hands and feet. Direct sequence analysis of genomic DNA demonstrated a homozygous 1984T > A (C653S) change in the DTDST gene in all patients. The clinically normal parents were heterozygous for the change. This is the first description of a homozygous C653S mutation of the DTDST gene. Hip dysplasia and patella hypermobility dominates the otherwise mild phenotype. These patients further expand the range of causative mutations in the DTD skeletal dysplasia family.
硫酸软骨素营养不良硫酸盐转运体（DTDST）基因突变会导致一系列骨骼发育不良疾病，其中包括致死性疾病（1B型软骨发育不全和2型肢骨发育异常）和非致死性疾病（硫酸软骨素营养不良和隐性多发性骨骺发育不良（rMED））。最常见的突变是R279W，纯合状态下会导致rMED，伴有双侧马蹄内翻足、MED和“双层”髌骨。我们描述了三名因DTDST基因中一个此前未报道的纯合突变导致rMED的患者。这三名患者（来自两个家庭）的父母均健康且非近亲结婚。所有患者在幼儿期均出现髋关节发育不良迹象，两名患者有复发性髌骨脱位发作。两名患者分别在13岁和14岁时接受了双侧全髋关节置换术。足部、外耳和腭部均正常。所有患者身高均正常。X线片显示股骨头发育不良、轻度全身性骨骺发育不良、髌骨骨化异常以及手足正常。对基因组DNA进行直接序列分析显示，所有患者的DTDST基因均存在纯合的1984T>A（C653S）变化。临床正常的父母为该变化的杂合子。这是首次对DTDST基因纯合C653S突变的描述。髋关节发育不良和髌骨活动度过大在其他方面表现轻微的表型中占主导地位。这些患者进一步扩大了DTD骨骼发育不良家族中致病突变的范围。
