Exome-based investigation of the genetic basis of human pigmentary glaucoma

Abstract

Background Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. Results Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. Conclusions We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.

GJA3 Genetic Variation and Autosomal Dominant Congenital Cataracts and Glaucoma Following Cataract Surgery

“…Several control populations were tested for the p.Asp67Tyr genetic variant in GJA3 . No instances of the p.Asp67Tyr genetic variant were identified in the exomes of 362 previously reported normal control participants from Iowa . Moreover, the p.Asp67Tyr genetic variant was not present in large public genomic databases including gnomAD (with >125 000 participants) and ClinVar, further supporting its pathogenicity.…”

A transcriptome atlas of the mouse iris at single-cell resolution defines cell types and the genomic response to pupil dilation

“…In mice, mutations in melanosomal genes lead to PDS, PG, and a related disorder, iris stromal atrophy ( Anderson et al, 2002 ). In humans, PDS also has a genetic component, but the contributing genes are still largely unknown ( Tandon et al, 2019 ; van der Heide et al, 2021 ). A conceptually similar disorder, exfoliation syndrome, is characterized by impaired pupil constriction and by the release of extracellular matrix material from the iris and lens, which accumulates in the trabecular meshwork and can lead to open angle glaucoma ( Kivelä, 2018 ; Schlötzer-Schrehardt, 2018 ; Tekin et al, 2020 ).…”

Thrombospondin Mutations and Patients With Primary Congenital Glaucoma in a United States Population

“…The entire coding sequence of THBS1 was subsequently examined for disease-causing mutations in 18 of 20 patients with PCG using whole-exome sequencing with standard methods as we have described 18 . Whole-exome sequence for the control subjects including coding sequence data for the THBS1 gene was obtained as part of a reported pigmentary glaucoma genetics research project 19 . Identified mutations were confirmed with Sanger sequencing and evaluated for potential pathogenicity using mutation analysis algorithms including PolyPhen-2, 20 SIFT, 21 MutationTaster, 22 CADD, 23 and BLOSUM62 24 …”

“…18 Whole-exome sequence for the control subjects including coding sequence data for the THBS1 gene was obtained as part of a reported pigmentary glaucoma genetics research project. 19 Identified mutations were confirmed with Sanger sequencing and evaluated for potential pathogenicity using mutation analysis algorithms including PolyPhen-2, 20 SIFT, 21 MutationTaster, 22 CADD, 23 and BLOSUM62. 24…”