Mutations in or near the transmembrane domain alter PMEL amyloid formation from functional to pathogenic. Academic Article uri icon


  • PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)--which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core--are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW-associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi-like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid.

published proceedings

  • PLoS Genet

altmetric score

  • 0.25

author list (cited authors)

  • Watt, B., Tenza, D., Lemmon, M. A., Kerje, S., Raposo, G., Andersson, L., & Marks, M. S.

citation count

  • 42

complete list of authors

  • Watt, Brenda||Tenza, Danièle||Lemmon, Mark A||Kerje, Susanne||Raposo, Graça||Andersson, Leif||Marks, Michael S

editor list (cited editors)

  • Jackson, I. J.

publication date

  • September 2011