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J Med Genet. 2014 Aug;51(8):518-25. doi: 10.1136/jmedgenet-2014-102351. Epub 2014 Jun 2.

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

Author information

1
The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China School of Life Sciences, Central South University, Changsha, Hunan, China.
2
Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
3
The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
4
Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
5
Department of Dermatology, Institute of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.
6
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.
7
The Xiangya Hospital, Central South University, Changsha, Hunan, China.
8
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.

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.

KEYWORDS:

Genetics; Genome-wide; Linkage; Myopia

PMID:
24891338
PMCID:
PMC4112430
DOI:
10.1136/jmedgenet-2014-102351
[Indexed for MEDLINE]
Free PMC Article

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