ArticleHuman molecular genetics2019
Non-Synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 2 of them syntheses that pooled it.
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Who cites it
26 citing papers in PubMed, 2 syntheses or guidelines pooled it, 66 citations in OpenAlex.
- Lack of Association betweenGenes · 2024Pooled it
- Pigment dispersion syndrome and pigmentary glaucoma: overview and racial disparities.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2023Pooled it
- Intraocular pressure induced blood retinal barrier compromise in mouse models and human glaucoma.Nature communications · 2026Article
- Atomic structure and in situ visualization of native PMEL lamellae in melanosomes.Nature communications · 2025Article
- Cryo-EM of wild-type and mutant PMEL amyloid cores reveals structural mechanism of pigment dispersion syndrome.Nature communications · 2025Article
- TLR4 deficiency does not alter glaucomatous progression in a mouse model of chronic glaucoma.Scientific reports · 2025Article
- Integrated Transcriptomic and Epigenomic Analysis Reveals Mechanisms Underlying Melanotic Spot Formation in Red Tilapia (International journal of molecular sciences · 2025Article
- Genetic Basis of Pigment Dispersion Syndrome and Pigmentary Glaucoma: An Update and Functional Insights.Genes · 2024Review
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- Observation of pH-Dependent Residual Structure in the Pmel17 Repeat Domain and the Implication for Its Amyloid Formation.Biochemistry · 2023Article
- Disrupting the Repeat Domain of Premelanosome Protein (PMEL) Produces Dysamyloidosis and Dystrophic Ocular Pigment Reflective of Pigmentary Glaucoma.International journal of molecular sciences · 2023Article
- The genetics of glaucoma: Disease associations, personalised risk assessment and therapeutic opportunities-A review.Clinical & experimental ophthalmology · 2022Review
- Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.Investigative ophthalmology & visual science · 2022Review
- Compound Heterozygous Variants of theFrontiers in genetics · 2022Article
- From Bench to Bed: The Current Genome Editing Therapies for Glaucoma.Frontiers in cell and developmental biology · 2022Review
- Melanosome Biogenesis in the Pigmentation of Mammalian Skin.Integrative and comparative biology · 2021Review
- Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Exome-based investigation of the genetic basis of human pigmentary glaucoma.BMC genomics · 2021Article
- Functional Domains and Evolutionary History of the PMEL and GPNMB Family Proteins.Molecules (Basel, Switzerland) · 2021Article
- Identification of critical amino acid residues in the regulatory N-terminal domain of PMEL.Scientific reports · 2021Article
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Authors and funding
18 authors at 6 institutions in 3 countries.
Funding
Abstract
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.
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