title: Griscelli syndrome: a model system to study vesicular trafficking.
abstract: Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutations in either the myosin VA (GS1), RAB27A (GS2) or melanophilin (GS3) genes. The three GS subtypes are commonly characterized by pigment dilution of the skin and hair, due to defects involving melanosome transport in melanocytes. Here, we review how detailed studies concerning GS have contributed to a better understanding of the molecular mechanisms involved in vesicle transport and membrane trafficking processes. Additionally, we demonstrate that the identification and biological analysis of novel disease-causing mutations highlighted the functional importance of the RAB27A-MLPH-MYO5A tripartite complex in intracellular melanosome transport. As the small GTPase Rab27a is able to interact with multiple effectors, including Slp2-a and Myrip, we report on their presumed role in melanosome transport. Furthermore, we summarize data suggesting that RAB27B and RAB27A are functionally redundant and hereby provide further insight into the pathogenesis of GS2. Finally, we discuss how the gathered knowledge about the RAB27A-MLPH-MYO5A tripartite complex can be translated into a possible therapeutic application to reduce (hyper)pigmentation of the skin.
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium. mireille.vangele@ugent.be
authors.forename: Mireille
authors.initials: M
authors.lastname: Van Gele
authors.forename: Peter
authors.initials: P
authors.lastname: Dynoodt
authors.forename: Jo
authors.initials: J
authors.lastname: Lambert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology*; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D020460:Melanosomes / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D024701:Myosin Type V / Q000235:genetics / Q000378:metabolism; D010858:Pigmentation / Q000235:genetics; D034622:RNA Interference; D013577:Syndrome; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C405804:EB1 microtubule binding proteins; C492410:MLPH protein, human; C501262:MYRIP protein, human; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; C077511:MYO5A protein, human; D024701:Myosin Type V; C066694:RAB27A protein, human; C512960:Rab27B protein, human; D018995:Myosin Heavy Chains; D020691:rab GTP-Binding Proteins