Cellular and clinical report of new Griscelli syndrome type III cases

Wendy Westbroek, Aharon Klar, Andrew R. Cullinane, Shira G. Ziegler, Haggit Hurvitz, Ashraf Ganem, Kirkland Wilson, Heidi Dorward, Marjan Huizing, Haled Tamimi, Igor Vainshtein, Yackov Berkun, Moran Lavie, William A. Gahl, Yair Anikster

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalPigment Cell and Melanoma Research
Volume25
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Keywords

  • Griscelli syndrome type III
  • Melanocyte
  • Melanophilin
  • Melanosome
  • Myosin-5a
  • RAB27A
  • Tripartite complex

ASJC Scopus subject areas

  • Oncology
  • General Biochemistry, Genetics and Molecular Biology
  • Dermatology

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