Cellular and clinical report of new Griscelli syndrome type III cases

Pigment Cell Melanoma Res. 2012 Jan;25(1):47-56. doi: 10.1111/j.1755-148X.2011.00901.x. Epub 2011 Oct 3.

Abstract

The RAB27A/Melanophilin/Myosin-5a tripartite protein complex is required for capturing mature melanosomes in the peripheral actin network of melanocytes for subsequent transfer to keratinocytes. Mutations in any one member of this tripartite complex cause three forms of Griscelli syndrome (GS), each with distinct clinical features but with a similar cellular phenotype. To date, only one case of GS type III (GSIII), caused by mutations in the Melanophilin (MLPH) gene, has been reported. Here, we report seven new cases of GSIII in three distinct Arab pedigrees. All affected individuals carried a homozygous missense mutation (c.102C>T; p.R35W), located in the conserved Slp homology domain of MLPH, and had hypomelanosis of the skin and hair. We report the first cellular studies on GSIII melanocytes, which demonstrated that MLPH(R35W) causes perinuclear aggregation of melanosomes in melanocytes, typical for GS. Additionally, co-immunoprecipitation assays showed that MLPH(R35W) lost its interaction with RAB27A, indicating pathogenicity of the R35W mutation.

Publication types

  • Case Reports
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Amino Acid Substitution
  • Arabs / genetics
  • Child
  • Child, Preschool
  • Consanguinity
  • Female
  • Hair Color / genetics*
  • Humans
  • Male
  • Melanocytes / metabolism
  • Melanocytes / ultrastructure
  • Melanosomes / metabolism*
  • Melanosomes / ultrastructure
  • Mutation, Missense*
  • Pedigree
  • Piebaldism / ethnology
  • Piebaldism / genetics*
  • Piebaldism / pathology
  • Pigmentation Disorders / ethnology
  • Pigmentation Disorders / genetics*
  • Pigmentation Disorders / pathology
  • Point Mutation*
  • Protein Interaction Mapping
  • Young Adult
  • rab GTP-Binding Proteins / physiology*
  • rab27 GTP-Binding Proteins

Substances

  • rab27 GTP-Binding Proteins
  • RAB27A protein, human
  • rab GTP-Binding Proteins

Supplementary concepts

  • Griscelli syndrome type 3