SLC39A5 mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia

Hui Guo, Xue Min Jin, Teng Fei Zhu, Tian Yun Wang, Ping Tong, Lei Tian, Yu Peng, Liang Dan Sun, Anran Wan, Jing Jing Chen, Yan Ling Liu, Ying Li, Qi Tian, Lu Xia, Lu Si Zhang, Yong Chen Pan, Li Na Lu, Qiong Liu, Lu Shen, Yun Ping LiWei Xiong, Jia Da Li, Bei Sha Tang, Yong Feng, Xue Jun Zhang, Zhuohua Zhang, Qian Pan, Zheng Mao Hu, Kun Xia

    Research output: Contribution to journalArticlepeer-review

    58 Citations (Scopus)


    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>G: p.Y47*) in SLC39A5 co-segregating with the phenotype in a non-syndromic severe high myopia family. The same nonsense mutation (c.141C>G:p.Y47*) was detected in a sporadic case and a missense mutation (c.911T>C:p. M304T) was identified and co-segregated in another family by screening additional cases. Both diseaseassociated 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.

    Original languageEnglish
    Pages (from-to)518-525
    Number of pages8
    JournalJournal of Medical Genetics
    Issue number8
    Publication statusPublished - 2014


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