Non-Synonymous Variants in the Premelanosome Protein (PMEL) Gene are Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Cause Biochemical Defects

Abstract

Pigmentary Glaucoma (PG) is a common glaucoma subtype that results from release of pigment from the iris (Pigment Dispersion Syndrome) and its deposition throughout the anterior chamber of the eye. Although PG has a substantial heritable component, no causative gene variants have yet been identified in humans. Whole Exome Sequencing (WES) of two independent pedigrees identified the first candidate gene for heritable PDS/PG - premelanosome protein (PMEL), which encodes a key component of the organelle (melanosome) essential for melanin synthesis, storage and transport. Targeted screening of PMEL in three independent replication cohorts (n= 394) identified nine additional PDS/PG-associated variants. These variants exhibited either defective post-translational processing of the PMEL (5/9), altered amyloid fibril formation (5/9), or both (3/9). Suppresion of the homologous pmela in zebrafish caused profound pigmentation and ocular defects further supporting PMEL’s role in PDS/PG. Taken together, these data support a model in which protein altering PMEL variants represent dominant negative mutations that impair PMEL’s normal ability to form functional amyloid fibrils. While PMEL mutations have previously been shown to cause pigmentation and ocular defects in animals, this research is the first report of mutations in PMEL that cause human eye disease.