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Hum Mol Genet. 2018 Dec 17. doi: 10.1093/hmg/ddy429. [Epub ahead of print]

Non-Synonymous variants in Premelanosome Protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma.

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Department of Medical Genetics, University of Alberta, Edmonton AB, Canada.
Department of Biological Sciences, University of Alberta, Edmonton AB, Canada.
Ocular Genomics Institute and Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Palm Beach Gardens, FL.
Anne Bates Leach Eye Hospital, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY.
Department of Ophthalmology, Flinders Medical Centre, Adelaide, South Australia.
Department of Ophthalmology, University of Alberta, Edmonton AB, Canada.


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 (WES) of two independent pedigrees to identify two PMEL variants associated with heritable PDS/PG. PMEL (premelanosome protein) 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 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.


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