PUBLICATION

Disrupting the Repeat Domain of Premelanosome Protein (PMEL) Produces Dysamyloidosis and Dystrophic Ocular Pigment Reflective of Pigmentary Glaucoma

Authors
Hodges, E.D., Chrystal, P.W., Footz, T., Doucette, L.P., Noel, N.C.L., Li, Z., Walter, M.A., Allison, W.T.
ID
ZDB-PUB-231015-60
Date
2023
Source
International Journal of Molecular Sciences   24(19): (Journal)
Registered Authors
Allison, Ted
Keywords
PMEL17, SILV, melanin, melanosome, pigment dispersion syndrome, prion-like, retina
MeSH Terms
  • Amyloid/metabolism
  • Animals
  • Eye/metabolism
  • Glaucoma, Open-Angle*/metabolism
  • Humans
  • Melanosomes/genetics
  • Melanosomes/metabolism
  • Neurodegenerative Diseases*/metabolism
  • Young Adult
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • gp100 Melanoma Antigen/genetics
PubMed
37833870 Full text @ Int. J. Mol. Sci.
Abstract
Pigmentary glaucoma has recently been associated with missense mutations in PMEL that are dominantly inherited and enriched in the protein's fascinating repeat domain. PMEL pathobiology is intriguing because PMEL forms functional amyloid in healthy eyes, and this PMEL amyloid acts to scaffold melanin deposition. This is an informative contradistinction to prominent neurodegenerative diseases where amyloid formation is neurotoxic and mutations cause a toxic gain of function called "amyloidosis". Preclinical animal models have failed to model this PMEL "dysamyloidosis" pathomechanism and instead cause recessively inherited ocular pigment defects via PMEL loss of function; they have not addressed the consequences of disrupting PMEL's repetitive region. Here, we use CRISPR to engineer a small in-frame mutation in the zebrafish homolog of PMEL that is predicted to subtly disrupt the protein's repetitive region. Homozygous mutant larvae displayed pigmentation phenotypes and altered eye morphogenesis similar to presumptive null larvae. Heterozygous mutants had disrupted eye morphogenesis and disrupted pigment deposition in their retinal melanosomes. The deficits in the pigment deposition of these young adult fish were not accompanied by any detectable glaucomatous changes in intraocular pressure or retinal morphology. Overall, the data provide important in vivo validation that subtle PMEL mutations can cause a dominantly inherited pigment pathology that aligns with the inheritance of pigmentary glaucoma patient pedigrees. These in vivo observations help to resolve controversy regarding the necessity of PMEL's repeat domain in pigmentation. The data foster an ongoing interest in an antithetical dysamyloidosis mechanism that, akin to the amyloidosis of devastating dementias, manifests as a slow progressive neurodegenerative disease.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping