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Terri L Young, Kristina Whisenhunt, Stuart Tompson, Reza Maroofian, Maryam Najafi, Abolfazl Rad; Whole-Genome Sequencing Identifies UTR Variants in LRPAP1 in a Large Iranian Family with High Myopia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):701.
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High myopia is defined as ≤ -6.00 diopters spherical equivalent, and is associated with a higher occurrence of retinal detachment. We sought to identify the causal gene mutations in a large geographically isolated Iranian high-grade myopia family (9 affected/4 unaffected) using whole-genome sequencing (WGS).
DNA was obtained from 8 affected/4 unaffected family members with refractive errors ranging from -12 to -29 diopters in at least one eye. WGS was performed on 4 distantly related affected individuals using 150 bp paired-end reads at 30X depth on an Illumina HiSeq X platform. Sequences were aligned to the UCSC hg19 human genome assembly using Isaac. Variants were called using Starling Variant Caller and annotated with Illumina Annotation Engine. Single nucleotide polymorphisms (SNPs) and insertion/deletion changes were filtered and analyzed using the SNP and Variation Suite software (Golden Helix). Ocular tissue gene expression data was available for LRPAP1 from our in-house microarray dataset, generated from healthy fetal (12- and 24-week gestation) and adult donor eyes using a mirVana total RNA extraction kit (Ambion) and HumanHT-12 v4 Expression BeadChips (Illumina).
WGS identified 19 coding variants. Two variants, g.3509483_3509484insA (rs34336383) and g.3513474C>G (rs189755673), were identified in the 3’-untranslated region (3’UTR) of the Low Density Lipoprotein Receptor-Related Protein-Associated Protein 1 (LRPAP1) gene in all 4 affected family members sequenced. Alternate allele frequencies (gnomAD database) were 0.245 and 0.002 in the general population, respectively. Microarray data showed LRPAP1 expression in all human fetal and adult ocular tissues examined (optic nerve, cornea, retina, RPE, choroid, and sclera). The highest expression signals were detected in fetal sclera, choroid, cornea, and adult cornea.
Homozygous truncating mutations in LRPAP1 have been causally implicated for the autosomal recessive myopia-23 (MYP23) locus on 4p16. In this large Iranian high myopia family, two 3’UTR variants were identified in LRPAP1. 3'UTR variants can destroy miRNA binding sites, resulting in translational inhibition or mRNA degradation, and subsequently reduced protein levels. Functional analyses will be performed using cellular and animal model systems to test the consequences of these variants.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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