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Original article
SLC39A5 mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia
  1. Hui Guo1,2,
  2. Xuemin Jin3,
  3. Tengfei Zhu1,
  4. Tianyun Wang1,
  5. Ping Tong4,
  6. Lei Tian3,
  7. Yu Peng1,
  8. Liangdan Sun5,
  9. Anran Wan1,
  10. Jingjing Chen1,
  11. Yanling Liu1,
  12. Ying Li1,
  13. Qi Tian1,
  14. Lu Xia1,
  15. Lusi Zhang1,
  16. Yongcheng Pan1,
  17. Lina Lu1,
  18. Qiong Liu1,
  19. Lu Shen1,
  20. Yunping Li1,4,
  21. Wei Xiong4,
  22. Jiada Li1,2,
  23. Beisha Tang6,
  24. Yong Feng6,
  25. Xuejun Zhang5,
  26. Zhuohua Zhang1,
  27. Qian Pan1,
  28. Zhengmao Hu1,2,
  29. Kun Xia1,2,7
  1. 1The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
  2. 2School of Life Sciences, Central South University, Changsha, Hunan, China
  3. 3Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  4. 4Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
  5. 5Department of Dermatology, Institute of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China
  6. 6The Xiangya Hospital, Central South University, Changsha, Hunan, China
  7. 7Key Laboratory of Medical Information Research, Changsha, Hunan, China
  1. Correspondence to Professor Kun Xia and Zhengmao Hu, The State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China; xiakun{at} and huzhengmao{at}


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 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.

  • Myopia
  • Genetics
  • Genome-wide
  • Linkage

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