TY - JOUR T1 - <em>SLC39A5</em> mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia JF - Journal of Medical Genetics JO - J Med Genet SP - 518 LP - 525 DO - 10.1136/jmedgenet-2014-102351 VL - 51 IS - 8 AU - Hui Guo AU - Xuemin Jin AU - Tengfei Zhu AU - Tianyun Wang AU - Ping Tong AU - Lei Tian AU - Yu Peng AU - Liangdan Sun AU - Anran Wan AU - Jingjing Chen AU - Yanling Liu AU - Ying Li AU - Qi Tian AU - Lu Xia AU - Lusi Zhang AU - Yongcheng Pan AU - Lina Lu AU - Qiong Liu AU - Lu Shen AU - Yunping Li AU - Wei Xiong AU - Jiada Li AU - Beisha Tang AU - Yong Feng AU - Xuejun Zhang AU - Zhuohua Zhang AU - Qian Pan AU - Zhengmao Hu AU - Kun Xia Y1 - 2014/08/01 UR - http://jmg.bmj.com/content/51/8/518.abstract N2 - Background High myopia, with the characteristic feature of refractive error, is one of the leading causes of blindness worldwide. It has a high heritability, but only a few causative genes have been identified and the pathogenesis is still unclear. Methods We used whole genome linkage and exome sequencing to identify the causative mutation in a non-syndromic high myopia family. Direct Sanger sequencing was used to screen the candidate gene in additional sporadic cases or probands. Immunofluorescence was used to evaluate the expression pattern of the candidate gene in the whole process of eye development. Real-time quantitative PCR and immunoblot was used to investigate the functional consequence of the disease-associated mutations. Results We identified a nonsense mutation (c.141C&gt;G:p.Y47*) in SLC39A5 co-segregating with the phenotype in a non-syndromic severe high myopia family. The same nonsense mutation (c.141C&gt;G:p.Y47*) was detected in a sporadic case and a missense mutation (c.911T&gt;C:p.M304T) was identified and co-segregated in another family by screening additional cases. Both disease-associated mutations were not found in 1276 control individuals. SLC39A5 was abundantly expressed in the sclera and retina across different stages of eye development. Furthermore, we found that wild-type, but not disease-associated SLC39A5 inhibited the expression of Smadl, a key phosphate protein in the downstream of the BMP/TGF-β (bone morphogenic protein/transforming growth factor-β) pathway. Conclusions Our study reveals that loss-of-function mutations of SLC39A5 are associated with the autosome dominant non-syndromic high myopia, and interference with the BMP/TGF-β pathway may be one of the molecular mechanisms for high myopia. ER -