Non-Synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma
| Autor: | W T Allison, Louis R. Pasquale, Michael A. Walter, Baojian Fan, Janey L. Wiggs, Tim Footz, David S. Greenfield, Keri F. Allen, Jamie E Craig, Robert Ritch, Gavin J. Neil, Richard K. Parrish, Kevin Linkroum, Kim Nguyen-Phuoc, Ordan J. Lehmann, Adrian Lahola-Chomiak, Shari Javadiyan, Ralf M. Leonhardt |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Amyloid Mutation Missense Iris Biology Dominant-Negative Mutation medicine.disease_cause 03 medical and health sciences Young Adult Exome Sequencing Genetics medicine Missense mutation Animals Humans Molecular Biology Gene Genetics (clinical) Exome sequencing Zebrafish Melanosome 0303 health sciences Mutation Melanosomes Pigmentation 030305 genetics & heredity General Medicine Middle Aged medicine.disease PMEL Pedigree Pigment dispersion syndrome Female sense organs General Article Glaucoma Open-Angle HeLa Cells gp100 Melanoma Antigen |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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