title: Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1).
abstract: Griscelli syndrome (GS) is a rare autosomal recessive disorder that associates hypopigmentation, characterized by a silver-gray sheen of the hair and the presence of large clusters of pigment in the hair shaft, and the occurrence of either a primary neurological impairment or a severe immune disorder. Two different genetic forms, GS1 and GS2, respectively, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin Va (MyoVa) cause GS1 and the dilute mutant in mice, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2 and the ashen mouse model. We herein present genetic and functional evidence that a third form of GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin (Mlph), the ortholog of the gene mutated in leaden mice. We also show that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis, which in part remain to be unraveled.
authors.affiliation: Unité de Recherhe sur le Développement Normal et Pathologique du Systéme Immunitaire, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Ménasché
authors.forename: Chen Hsuan
authors.initials: CH
authors.lastname: Ho
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Jérôme
authors.initials: J
authors.lastname: Feldmann
authors.forename: Ilhan
authors.initials: I
authors.lastname: Tezcan
authors.forename: Fügen
authors.initials: F
authors.lastname: Ersoy
authors.forename: Anne
authors.initials: A
authors.lastname: Houdusse
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D006197:Hair / Q000473:pathology; D006801:Humans; D017496:Hypopigmentation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020460:Melanosomes / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D024701:Myosin Type V / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D013577:Syndrome; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C492410:MLPH protein, human; C435724:Mlph protein, mouse; C513082:Myo5a protein, mouse; D000075745:rab27 GTP-Binding Proteins; C077511:MYO5A protein, human; D004247:DNA; D024701:Myosin Type V; C066694:RAB27A protein, human; C512962:Rab27a protein, mouse; D018995:Myosin Heavy Chains; D020691:rab GTP-Binding Proteins