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.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

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Free PMC article

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

Hui Guo et al. J Med Genet.2014 Aug.
Free PMC article

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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Figures

Figure 1
Figure 1
Identification ofSLC39A5 mutations in high myopia patients. (A) The pedigree plot for HM-FR3: solid symbols represent affected individuals. M numbers denote individuals whose DNA samples were analysed. The nonsense mutation (Y47X) identified by whole genome linkage and exome sequencing segregated with the phenotype exactly. (B) Fundus photograph for the proband of HM-FR3 (M16346) appeared tigroid and had focal atrophy of the choroid. OD represents right eye and OS represents left eye. (C) Multi-point parametric linkage analysis shows four regions with LOD score more than 1 on chromosome 2, 10, and 12, respectively, and other eight low peaks with maximum LOD score no more than 0.5. (D) The pedigree plot for family HM-ZZ19 with the missense mutation (M304T) ofSLC39A5. (E) Schematic of human SLC39A5 protein structure and mutational locations: the nonsense mutation occurred at the 47th amino acid and is located in the amino-terminal domain; the missense mutation is located at the terminal of the third transmembrane domain.
Figure 2
Figure 2
Slc39a5 is expressed in all stages of developing mouse eye, mainly in the sclera and retina. (A) Immunofluorescent labelling of Slc39a5 at different developing stages of normal mouse eye. The localisation of Slc39a5 is shown by the green colour, and the blue colour indicates the nuclei that were stained with DAPI. We selected four developing stages of normal mouse, E10, P0, P13, and adult. Slc39a5 is abundantly expressed at different developing stages of the eye. (B) The enlargement of the retina and sclera from labelled adult mouse eye. Slc39a5 is abundantly expressed at the sclera and different layers of the retina. The following abbreviations represent the retinal layers: NFL, nerve fibre layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; IS, inner segment; OS, outer segment ; PRL, photo receptor layer; and RPE, retinal pigment epithelium.
Figure 3
Figure 3
Disease-associated mutations ofSLC39A5 failed to suppress Smad1 expression. (A, B) Real-time quantitative PCR and immunoblot analysis showed a pronounced increase of both mRNA (A) and protein (B) expression level of Smad1 in two affected individuals (M16346 and M16350) as compared to controls. (C) Immunoblot analysis showed that wild-type SLC39A5 suppressed Smad1 expression; however, both disease-associated mutations notably up-regulated Smad1expression in transduced HEK293 cell lines. (D, E). Immunoblot analysis showed that SLC39A5 shRNAs (SH1, SH2, SH3) (D) notably attenuated the suppressive effect of wild-type SLC39A5 on Smad1 expression (E).
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