title: SLC39A5 mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia.
abstract: 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.
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China School of Life Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Jin
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhu
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Tong
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Dermatology, Institute of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Liangdan
authors.initials: L
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Anran
authors.initials: A
authors.lastname: Wan
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xia
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Lusi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Pan
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China School of Life Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Jiada
authors.initials: J
authors.lastname: Li
authors.affiliation: The Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Beisha
authors.initials: B
authors.lastname: Tang
authors.affiliation: The Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Dermatology, Institute of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China School of Life Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Hu
authors.affiliation: The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China School of Life Sciences, Central South University, Changsha, Hunan, China Key Laboratory of Medical Information Research, Changsha, Hunan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004622:Embryo, Mammalian / Q000737:chemistry; D005123:Eye / Q000737:chemistry / Q000254:growth & development; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009216:Myopia / Q000235:genetics*; D010375:Pedigree; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D027682:Cation Transport Proteins; C521171:SLC39A5 protein, human; D016212:Transforming Growth Factor beta
keywords: Genetics; Genome-wide; Linkage; Myopia