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Pigmentary glaucoma (PG) is a common glaucoma subtype that results from release of pigment from the iris, called pigment dispersion syndrome (PDS), and its deposition throughout the anterior chamber of the eye. Although PG has a substantial heritable component, no causative genes have yet been identified. We used whole exome sequencing of two independent pedigrees to identify two premelanosome protein ( PMEL)  variants associated with heritable PDS/PG.  PMEL  encodes a key component of the melanosome, the organelle essential for melanin synthesis, storage and transport. Targeted screening of  PMEL  in three independent cohorts ( n  = 394) identified seven additional PDS/PG-associated non-synonymous variants. Five of the nine variants exhibited defective processing of the PMEL protein. In addition, analysis of PDS/PG-associated  PMEL  variants expressed in HeLa cells revealed structural changes to pseudomelanosomes indicating altered amyloid fibril formation in five of the nine variants. Introduction of 11-base pair deletions to the homologous  pmela  in zebrafish by the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 method caused profound pigmentation defects and enlarged anterior segments in the eye, further supporting PMEL’s role in ocular pigmentation and function. Taken together, these data support a model in which missense  PMEL  variants represent dominant negative mutations that impair the ability of PMEL 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  causing human disease.

Non-Synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma