Pigment Dispersion Syndrome and Pigmentary Glaucoma Associated Variants in Premelanosome Protein (PMEL) Cause Protein Processing and Fibrillogenesis Defects

Abstract

Purpose : Pigment Dispersion Syndrome (PDS) is the shedding of pigment from the posterior surface of the iris into the anterior chamber, which in some cases can progress to elevated IOP and retinal ganglion cell death termed Pigmentary Glaucoma (PG). The genetic etiology of PDS/PG has remained elusive despite years of study suggesting a strong heritable component. We have recently identified several functionally impactful protein coding PMEL variants associated with PG in humans. These results provide insight into the genetic etiology of PDS/PG, allowing for rationally designed therapeutics and treatments to be developed for this important cause of blindness.

Methods : PMEL was identified as a candidate gene for PDS/PG through Whole Exome Sequencing (WES) of patients from two affected families. 7 additional PMEL variants were identified through screening three independent cohorts of unrelated patients (n=395 total unrelated patients) affected with PG. We are using molecular and cell biology techniques to investigate how these PDS/PG-associated PMEL variants affect the processing, trafficking, and function of PMEL protein in vitro.

Results : Nine PMEL variants found in PDS/PG patients were functionally characterized using immunoblotting, subcellular localization analysis, and ultrastructural analysis using Transmission Electron Microscopy (TEM). Although subcellular localization was not altered, functional analyses of these variants have revealed potentially damaging defects. Protein processing defects were observed when protein blots were probed with either a C-terminal antibody (1/9 variants) or a mature sialylation-specific antibody (5/9 variants). Ultrastructural analysis with TEM is currently underway but all variants examined exhibit disrupted fibrillogenesis (4/4 variants).

Conclusions : We report the first discovery of a gene for PDS/PG in humans. However, PMEL variants were only detected in a subset of PDS/PG patients supporting the previous observations of genetic heterogeneity. Elucidating the molecular etiology of PDS/PG opens the door to the first rationally designed therapeutics and treatments for PDS/PG, and may provide insight into the underlying pathology of this disease, which hereto has been controversial. Our data support a melanocyte centric model of PDS/PG, with the initial pigment shedding because of melanocyte dysfunction.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.