Sheffield V C, Kraiem Z, Beck J C, Nishimura D, Stone E M, Salameh M, Sadeh O, Glaser B
Department of Pediatrics, University of Iowa, Iowa City 52242, USA.
Nat Genet. 1996 Apr;12(4):424-6. doi: 10.1038/ng0496-424.
Exactly 100 years ago, in 1896, Pendred first described the association of congenital deafness with thyroid goitre (MM#274600). The incidence of Pendred syndrome is estimated at 7.5-10/100,000, and may be responsible for as much as 10% of hereditary deafness. The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. The reason for the association between the thyroid and cochlear defects is similarly obscure, leading some investigators to suggest that the two recessive defects may be occurring together by chance in highly consanguineous families. An in vivo defect in thyroid iodine organification in Pendred syndrome patients has been reported. However, the molecular basis of this defect is unknown and the presence of an intrinsic thyroidal defect has not been conclusively demonstrated. We have adopted a genetic linkage study as a first step towards identifying the gene. The availability of an inbred Pendred syndrome kindred allowed us to utilize an efficient DNA pooling strategy to perform a genome-wide linkage search for the disease locus. In this way, we have mapped the disease locus to an approximately 9-cM interval between GATA23F5 and D7S687 on chromosome 7. In addition, we demonstrate an intrinsic thyroid iodine organification defect in a patient's thyroid cells as the cause of the thyroid dysfunction.
整整100年前，即1896年，彭德雷德首次描述了先天性耳聋与甲状腺肿的关联（MM#274600）。彭德雷德综合征的发病率估计为7.5 - 10/100,000，可能占遗传性耳聋的10%。尽管一些患者存在耳蜗的蒙迪尼型畸形，但彭德雷德综合征中先天性耳聋的病因仍不清楚。甲状腺与耳蜗缺陷之间关联的原因同样不明，这使得一些研究者认为这两种隐性缺陷可能在高度近亲结婚的家庭中偶然同时出现。有报道称彭德雷德综合征患者存在甲状腺碘有机化的体内缺陷。然而，这种缺陷的分子基础尚不清楚，且甲状腺内在缺陷的存在也未得到确凿证实。我们采用了基因连锁研究作为鉴定该基因的第一步。一个近亲繁殖的彭德雷德综合征家族使我们能够利用一种高效的DNA池策略对疾病位点进行全基因组连锁搜索。通过这种方式，我们已将疾病位点定位到7号染色体上GATA23F5和D7S687之间大约9厘摩的区间内。此外，我们证明了患者甲状腺细胞中存在甲状腺碘有机化内在缺陷是甲状腺功能障碍的原因。
