title: A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome.
abstract: The autosomal recessive Griscelli syndrome type II (GSII) is caused by mutations in the RAB27A gene. Typical clinical features include immunological impairment, silver-gray scalp hair, eyelashes and eyebrows and hypomelanosis of the skin. Rabs help determine the specificity of membrane trafficking steps within cells. In melanocytes, the GTP-bound form of Rab27A associates with the membranes of mature fully-pigmented melanosomes through its geranylgeranyl group. Once attached, Rab27A recruits the downstream effector Melanophilin (Mlph) and the actin-dependent motor protein Myosin Va (MyoVa). The molecular Rab27A/Mlph/MyoVA tripartite complex, which links melanosomes to the peripheral actin network, is required to achieve melanosome transfer to surrounding keratinocytes in the epidermis. Here we report a novel homozygous missense mutation c.127G>A, p.G43S in exon 2 of the RAB27A gene of an Afghani GSII patient. Laser scanning confocal microscopy showed that the G43S mutation, which is located in the highly conserved switch I region of Rab27A, induces perinuclear localization of melanosomes in normal melanocytes, and fails to restore melanosomes to the actin-rich periphery in GSII melanocytes. Co-immunoprecipitation studies showed that Rab27A(G43S) fails to interact with its effector Melanophilin, indicating that the switch I region functions in the recruitment of Rab effector proteins.
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. wwestbro@mail.nih.gov
authors.forename: Wendy
authors.initials: W
authors.lastname: Westbroek
authors.forename: Maya
authors.initials: M
authors.lastname: Tuchman
authors.forename: Bradford
authors.initials: B
authors.lastname: Tinloy
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.forename: Jens M
authors.initials: JM
authors.lastname: Hertz
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Carsten
authors.initials: C
authors.lastname: Heilmann
authors.forename: Amanda
authors.initials: A
authors.lastname: Helip-Wooley
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000346:Afghanistan; D020816:Amino Acid Motifs; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000737:chemistry / Q000378:metabolism; D020460:Melanosomes / Q000737:chemistry / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D016415:Sequence Alignment; D013577:Syndrome; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C492410:MLPH protein, human; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins