SLC39A5mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia

Abstract

BackgroundHigh 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

“…Population-based epidemiological investigations found that the disease is associated with environmental risk factors, such as a close reading distance and less outdoor activity (8,9). With the advent of nextgeneration sequencing, a few of disease genes have been discovered in recent years (18)(19)(20)(21)(22)(23)(24). Because myopia is dependent on both genetics and lifestyle and preschool children have less exposure to environmental risks, we designed this study using a special cohort with EOHM.…”

“…Of note, the identified genetic contributions of the dozens of loci and genes to myopia are very limited. To date, based on pedigree studies with next-generation sequencing, several disease-causing genes have been discovered, including two recessive genes, LRPAP1 (18) and LEPREL1 (19); four dominant genes, ZNF644 (20), SCO2 (21), SLC39A5 (22), and P4HA2 (23); and one X-linked gene, ARR3 (24). However, a large-scale screening of these genes in HM cohorts provided evidence that only a small proportion (<5%) of HM patients harbor mutations in these known genes, which can be attributed to as-yetunidentified causative genes (25).…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…ZIP5 is also expressed during the whole process of eye development, mainly in the sclera and retina (133). Zinc mediated by ZIP5 is likely to be involved in the regulation of Smad protein expression (133). Complete disruption of the Zip5 gene in mice, and intestine-or pancreas-specific disruption of the Zip5 gene in mice, clearly indicates that ZIP5 participates in the control of zinc excretion.…”

“…ZIP5 is abundantly expressed in the small intestine and pancreas (83). ZIP5 is also expressed during the whole process of eye development, mainly in the sclera and retina (133). Zinc mediated by ZIP5 is likely to be involved in the regulation of Smad protein expression (133).…”

“…Nonsense and missense mutations of ZIP5/SLC39A5 have recently been shown to be associated with nonsyndromic high myopia (133), which may be caused in an autosomal dominant or haploinsufficient manner.…”