ZFIN ID: ZDB-PUB-181219-11
Non-Synonymous variants in Premelanosome Protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma
Lahola-Chomiak, A.A., Footz, T., Nguyen-Phuoc, K., Neil, G.J., Fan, B., Allen, K.F., Greenfield, D.S., Parrish, R.K., Linkroum, K., Pasquale, L.R., Leonhardt, R.M., Ritch, R., Javadiyan, S., Craig, J.E., Ted Allison, W., Lehmann, O.J., Walter, M.A., Wiggs, J.L.
Date: 2018
Source: Human molecular genetics   28(8): 1298-1311 (Journal)
Registered Authors: Allison, Ted, Lehmann, Ordan J.
Keywords: none
MeSH Terms:
  • Adult
  • Amyloid/metabolism
  • Animals
  • Female
  • Glaucoma, Open-Angle/genetics*
  • HeLa Cells
  • Humans
  • Iris/metabolism
  • Male
  • Melanosomes/genetics
  • Middle Aged
  • Mutation, Missense/genetics
  • Pedigree
  • Pigmentation/genetics
  • Whole Exome Sequencing/methods
  • Young Adult
  • Zebrafish
  • gp100 Melanoma Antigen/genetics*
  • gp100 Melanoma Antigen/physiology*
PubMed: 30561643 Full text @ Hum. Mol. Genet.
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.