title: Cellular and clinical report of new Griscelli syndrome type III cases.
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.
authors: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA. wwestbro@mail.nih.gov
authors: Wendy
authors: W
authors: Westbroek
authors: Aharon
authors: A
authors: Klar
authors: Andrew R
authors: AR
authors: Cullinane
authors: Shira G
authors: SG
authors: Ziegler
authors: Haggit
authors: H
authors: Hurvitz
authors: Ashraf
authors: A
authors: Ganem
authors: Kirkland
authors: K
authors: Wilson
authors: Heidi
authors: H
authors: Dorward
authors: Marjan
authors: M
authors: Huizing
authors: Haled
authors: H
authors: Tamimi
authors: Igor
authors: I
authors: Vainshtein
authors: Yackov
authors: Y
authors: Berkun
authors: Moran
authors: M
authors: Lavie
authors: William A
authors: WA
authors: Gahl
authors: Yair
authors: Y
authors: Anikster
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D018912:Arabs / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D006200:Hair Color / Q000235:genetics*; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure; D020460:Melanosomes / Q000378:metabolism* / Q000648:ultrastructure; D020125:Mutation, Missense; D010375:Pedigree; D016116:Piebaldism / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D010859:Pigmentation Disorders / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D025941:Protein Interaction Mapping; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins