Cellular and clinical report of new Griscelli syndrome type III cases

Authors

  • Wendy Westbroek,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Aharon Klar,

    1.  Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Andrew R. Cullinane,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Shira G. Ziegler,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Haggit Hurvitz,

    1.  Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Ashraf Ganem,

    1.  Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Kirkland Wilson,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Heidi Dorward,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Marjan Huizing,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Haled Tamimi,

    1.  Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Igor Vainshtein,

    1.  Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Yackov Berkun,

    1.  Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine Tel-Aviv University, Tel-Aviv, Israel
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  • Moran Lavie,

    1.  Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine Tel-Aviv University, Tel-Aviv, Israel
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  • William A. Gahl,

    1.  Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
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  • Yair Anikster

    1.  Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine Tel-Aviv University, Tel-Aviv, Israel
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W. Westbroek, e-mail: wwestbro@mail.nih.gov

Summary

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.

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