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PLoS genetics2011; 7(9); e1002286; doi: 10.1371/journal.pgen.1002286

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

Abstract: 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.
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Publication Date: 2011-09-15 PubMed ID: 21949659PubMed Central: PMC3174235DOI: 10.1371/journal.pgen.1002286Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study investigates how changes within or near the transmembrane domain (TMD) of PMEL protein cause a shift from functional to harmful amyloid fibril formation impacting pigmentation. The researchers propose that these mutations can offer insight into the transformation from physiological to pathological amyloid.

Introduction and Background

  • PMEL is a protein specific to pigment cells that forms physiological amyloid fibrils. These fibrils provide a structure where melanin, the pigment responsible for hair, skin, and eye color, deposits.
  • Minor mutations of PMEL, i.e. hypomorphic mutations have been known to result in a slight pigment dilution that is recessively inherited.
  • However, alleles or variants of PMEL found in certain species, such as the Dominant white chicken (DW) and Silver horse (HoSi), carry mutations that change the TMD and are thus outside the amyloid core. These mutations cause a significant loss in pigmentation, inherited dominantly.

Research Findings

  • Observations revealed that mutations within Dominant white chicken (DW) and Silver horse (HoSi) alter PMEL TMD oligomerization, i.e. the process of a few molecules combining to form a complex, and/or their association with membranes. This results in formation of aberrantly packed fibrils.
  • The malfunctioning fibrils were associated with pigmentation loss in cultured melanocytes, implying they inhibit melanin production and/or the integral function of melanosomes responsible for pigment synthesis and transport.
  • The research also discovered that secondary changes found in the Smoky chicken and Dun chicken, which counteract the dominant DW phenotype, prevent PMEL from accumulating in fibrillogenic compartments. This consequently obstructs DW-associated pigment loss.

Conclusions

  • Based on these findings, it has been proposed that the mutations in TMD found in DW and HoSi breeds alter the usual non-pathogenic form of amyloid fibrils to become harmful (pathogenic), thereby inhibiting melanosome function.
  • The secondary mutations in Smoky and Dun chickens behave as null alleles, preventing the formation of malfunctioning fibrils, thus they neutralize or dampen the harmful effects caused by the previous mutations.
  • Researchers suggest that by studying PMEL mutations, we can gain deeper understanding into the process of physiological to pathological conversion of amyloid fibrils. Such insights may assist in learning more about human conditions, such as Alzheimer’s and other amyloid-related diseases.

Cite This Article

APA
Watt B, Tenza D, Lemmon MA, Kerje S, Raposo G, Andersson L, Marks MS. (2011). Mutations in or near the transmembrane domain alter PMEL amyloid formation from functional to pathogenic. PLoS Genet, 7(9), e1002286. https://doi.org/10.1371/journal.pgen.1002286

Publication

PLoS genetics
ISSN: 1553-7404
NlmUniqueID: 101239074
Country: United States
Language: English
Volume: 7
Issue: 9
Pages: e1002286
PII: e1002286

Researcher Affiliations

Watt, Brenda
  • Department of Pathology and Laboratory Medicine and Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Tenza, Danièle
    Lemmon, Mark A
      Kerje, Susanne
        Raposo, Graça
          Andersson, Leif
            Marks, Michael S

              MeSH Terms

              • Amino Acid Sequence
              • Amyloid / biosynthesis
              • Amyloid / genetics
              • Animals
              • Cells, Cultured
              • Chickens
              • HeLa Cells
              • Horses
              • Humans
              • Melanins / biosynthesis
              • Melanins / genetics
              • Melanocytes / ultrastructure
              • Melanosomes / genetics
              • Melanosomes / ultrastructure
              • Membrane Glycoproteins / genetics
              • Membrane Glycoproteins / metabolism
              • Mice
              • Molecular Sequence Data
              • Mutation
              • Pigmentation / genetics
              • Protein Structure, Tertiary / genetics
              • Sequence Homology, Amino Acid
              • gp100 Melanoma Antigen / genetics
              • gp100 Melanoma Antigen / metabolism

              Grant Funding

              • R01 AR048155 / NIAMS NIH HHS
              • R01 AR048155-08 / NIAMS NIH HHS
              • T32 GN997229 / PHS HHS
              • F31 GM08917 / NIGMS NIH HHS

              Conflict of Interest Statement

              The authors have declared that no competing interests exist.

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