Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene:: correlation between sulfate transport activity and chondrodysplasia phenotype
Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene:: correlation between sulfate transport activity and chondrodysplasia phenotype
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DOI：
10.1093/hmg/10.14.1485
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发表时间：
2001-07-01
影响因子：
3.5
通讯作者：
Karniski, LP
中科院分区：
文献类型：
--
作者：
Karniski, LP
骨发育不良硫酸盐转运蛋白（DTDST）基因编码一种跨膜蛋白，将硫酸盐转运到软骨细胞中以维持蛋白聚糖的充分硫酸化。该基因的突变导致四种遗传性软骨发育不良，包括畸形性发育不良、多发性骨骺发育不良、骨发育不全2型和软骨发育不全1B（ACG-1B）。为了确定在这些软骨发育不良的个体中发现的DTDST突变是否在功能上彼此不同，我们比较了11个报告的DTDST突变的硫酸盐转运活性。五个突变，G255 E，Δ a1751，L483 P，R178 X和N425 D，有最小的硫酸盐转运功能后表达在非洲爪蟾卵母细胞。两个突变，三角洲V340和R279 W，运输硫酸盐的速率分别为17%和32%，野生型DTDST。四个突变，A715 V，C653 S，Q454 P和G678 V，硫酸盐转运率几乎等于野生型DTDST。转运动力学没有不同的四个突变与近正常的硫酸盐转运功能和野生型DTDST。当根据一般表型对不同DTDST突变的硫酸盐转运功能进行分组时，具有最严重形式ACG-1B的个体往往是无效突变的纯合型，具有中度严重骨骼发育不全2型的个体具有至少一个具有功能丧失突变的等位基因，并且具有最温和形式的个体通常是具有残余硫酸盐转运功能的突变的纯合型。然而，在非洲爪蟾卵母细胞表达系统中，残余转运功能与表型严重程度之间的相关性不是绝对的，这表明除了DTDST蛋白的内在硫酸盐转运特性之外，其他因素可能影响DTDST突变个体的表型。
The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. Mutations in this gene are responsible for four recessively inherited chondrodysplasias that include diastrophic dysplasia, multiple epiphyseal dysplasia, atelosteogenesis type 2 and achondrogenesis 1B (ACG-1B). To determine whether the DTDST mutations found in individuals with these chondrodysplasias differ functionally from each other, we compared the sulfate transport activity of 11 reported DTDST mutations. Five mutations, G255E, Delta a1751, L483P, R178X and N425D, had minimal sulfate transport function following expression in Xenopus laevis oocytes. Two mutations, Delta V340 and R279W, transported sulfate at rates of 17 and 32%, respectively, of wild-type DTDST. Four mutations, A715V, C653S, Q454P and G678V, had rates of sulfate transport nearly equal to that of wild-type DTDST. Transport kinetics were not different among the four mutations with near-normal sulfate transport function and wild-type DTDST. When the sulfate transport function of the different DTDST mutations are grouped according to the general phenotypes, individuals with the most severe form, ACG-1B, tend to be homozygous for null mutations, individuals with the moderately severe atelosteogenesis type 2 have at least one allele with a loss-of-function mutation, and individuals with the mildest forms are typically homozygous for mutations with residual sulfate transport function. However, in the X.laevis oocyte expression system, the correlation between residual transport function and the severity of phenotype was not absolute, suggesting that factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations.