Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 Novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance
Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 Novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance
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DOI：
10.1002/humu.1.abs
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发表时间：
2001-01-01
期刊：
影响因子：
3.9
通讯作者：
Superti-Furga, A
中科院分区：
文献类型：
--
作者：
Rossi, A;Superti-Furga, A
DTDST 基因突变可导致一系列骨骼发育不良疾病，其中包括两种致命性疾病：1B 型软骨发育不良 (ACG1B) 和 2 型软骨发育不良 (AO2)；以及两种非致命性疾病：骨性发育不良（DTD）和隐性多发性骨骺发育不良（rMED）。基因产物是细胞膜的硫酸盐-氯化物交换剂。硫酸盐交换剂的失活导致细胞内硫酸盐耗尽，并导致软骨细胞和成纤维细胞等易受影响的细胞中合成硫酸不足的蛋白聚糖。基因型-表型相关性是可识别的，预测截短的蛋白质或跨膜结构域中的非保守氨基酸取代的突变会产生严重的表型，非跨膜氨基酸取代和剪接位点突变会产生较温和的表型。临床表型严格受残余活性程度的调节。已观察到 30 多种突变，其中报告了 22 种新突变。最常见的突变 862C>T (R279W) 是一种轻度突变，当纯合时产生 rMED 表型，当复合时则大多为 DTD； CpG 二核苷酸的出现及其泛民族分布表明独立复发，突变 IVS1+2T>C 是第二常见的突变，但在芬兰非常常见。它产生低水平的正确剪接的 mRNA，并在纯合时导致 DTD。另外两种突变，1045-1047delGTT (V340del) 和 558C>T (R178X)，与严重表型相关，并已在多名患者中观察到。大多数其他突变都很罕见。杂合子在临床上不受影响。当分析前对临床样本进行与ACG1B/AO2/DTD/rMED谱兼容的放射学和组织学特征筛查时，突变检出率很高（等位基因的90%以上），并且可以提供适当的遗传咨询。培养的成纤维细胞中的硫酸盐吸收或硫酸盐掺入在很大程度上已被突变分析所取代，但在突变分析无法提供信息的情况下仍然可能有用。尽管向患者的培养细胞补充硫醇可能会绕过转运蛋白缺陷并增强蛋白聚糖的硫酸化，但目前尚无治疗方法。正在开发这种和其他硫酸盐代谢紊乱的小鼠模型，以帮助开发治疗方法。 Hum Mutat 17:159-171, 2001。(C) 2001 Wiley-Liss, Inc.
Mutations in the DTDST gene can result in a family of skeletal dysplasia conditions which comprise two lethal disorders, achondrogenesis type 1B (ACG1B) and atelosteogenesis type 2 (AO2); and two non-lethal disorders, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia (rMED). The gene product is a sulfate-chloride exchanger of the cell membrane. Inactivation of the sulfate exchanger leads to intracellular sulfate depletion and to the synthesis of undersulfated proteoglycans in susceptible cells such as chondrocytes and fibroblasts. Genotype-phenotype correlations are recognizable, with mutations predicting a truncated protein or a non-conservative amino acid substitution in a transmembrane domain giving the severe phenotypes, and non transmembrane amino acid substitutions and splice site mutations giving the milder phenotypes. The clinical phenotype is modulated strictly by the degree of residual activity. Over 30 mutations have been observed, including 22 novel mutations reported here. The most frequent mutation, 862C>T (R279W), is a mild mutation giving the rMED phenotype when homozygous and mostly DTD when compounded; occurrence at a CpG dinucleotide and its panethnic distribution suggest independent recurrence, Mutation IVS1+2T>C is the second most common mutation, but is very frequent in Finland. It produces low levels of correctly spliced mRNA, and results in DTD when homozygous. Two other mutations, 1045-1047delGTT (V340del) and 558C>T (R178X), are associated with severe phenotypes and have been observed in multiple patients. Most other mutations are rare. Heterozygotes are clinically unaffected. When clinical samples are screened for radiologic and histologic features compatible with the ACG1B/AO2/ DTD/rMED spectrum prior to analysis, the mutation detection rate is high (over 90% of alleles), and appropriate genetic counseling can be given. The sulfate uptake or sulfate incorporation as says in cultured fibroblasts have largely been replaced by mutation analysis, but may still be useful in cases where mutation analysis is not informative. Although supplementation of patients' cultured cells with thiols may bypass the transporter defect and enhance sulfation of proteoglycans, therapeutic approaches are not yet available. Mouse models for this and other disorders of sulfate metabolism are being developed to help in developing therapeutic treatments. Hum Mutat 17:159-171, 2001. (C) 2001 Wiley-Liss, Inc.