Hästbacka J, de la Chapelle A, Mahtani M M, Clines G, Reeve-Daly M P, Daly M, Hamilton B A, Kusumi K, Trivedi B, Weaver A
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Massachusetts 02142.
Cell. 1994 Sep 23;78(6):1073-87. doi: 10.1016/0092-8674(94)90281-x.
Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.
脊柱骨骺发育不良（DTD）是一种特征明确的常染色体隐性骨软骨发育不良症，其临床特征包括侏儒症、脊柱变形和特定关节异常。该疾病在大多数人群中都有发生，但由于明显的奠基者效应，在芬兰尤为普遍。DTD基因定位于5号染色体长臂远端，基于对芬兰人群的连锁不平衡研究，我们之前预测DTD基因应位于距集落刺激因子1受体（CSF1R）基因座约64 kb处。在此，我们通过精细结构连锁不平衡定位报告了DTD基因的位置克隆。该基因位于预测位置，在CSF1R基因近端约70 kb处，编码一种新型硫酸盐转运蛋白。其产物功能受损可能导致软骨基质中蛋白聚糖硫酸化不足，从而引发该疾病的临床表型。这些结果证明了连锁不平衡定位在隔离人群中进行位置克隆的强大作用。
