title: Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A.
abstract: Griscelli syndrome (GS), a rare autosomal recessive disorder, is characterized by partial albinism, along with immunologic abnormalities or severe neurological impairment or both. Mutations in one of two different genes on chromosome 15q can cause the different subtypes of GS. Most patients with GS display the hemophagocytic syndrome and have mutations in RAB27A, which codes for a small GTPase. Two patients with neurological involvement have mutations in MYO5A, which codes for an actin-based molecular motor. The RAB27A and MYO5A gene products interact with each other and function in vesicle trafficking. We report the molecular basis of GS in a Muslim Arab kindred whose members have extremely variable neurological involvement, along with the hemophagocytic syndrome and immunologic abnormalities. The patients have normal MYO5A genes but exhibit a homozygous 67.5-kb deletion that eliminates RAB27A mRNA and immunocytofluorescence-detectable protein. We also describe the molecular organization of RAB27A and a multiplex polymerase chain reaction assay for the founder deletion in this kindred. Finally, we propose that all patients with GS have RAB27A mutations and immunologic abnormalities that sometimes result in secondary neurological involvement. The two patients described elsewhere who have MYO5A mutations and neurological complications but no immunologic defects may not have GS but instead may have Elejalde syndrome, a condition characterized by mild hypopigmentation and severe, primary neurological abnormalities.
authors.affiliation: Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, 10 Center Drive, Bethesda, MD 20892-1830, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Paul D
authors.initials: PD
authors.lastname: Anderson
authors.forename: Diana L
authors.initials: DL
authors.lastname: Fitzpatrick
authors.forename: Aharon
authors.initials: A
authors.lastname: Klar
authors.forename: Eva
authors.initials: E
authors.lastname: Gross-Kieselstein
authors.forename: Yackov
authors.initials: Y
authors.lastname: Berkun
authors.forename: Gila
authors.initials: G
authors.lastname: Shazberg
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Haggit
authors.initials: H
authors.lastname: Hurvitz
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D005347:Fibroblasts; D019084:Fluorescent Antibody Technique, Indirect; D018740:Genetic Heterogeneity; D006801:Humans; D008969:Molecular Sequence Data; D009218:Myosins / Q000235:genetics*; D017384:Sequence Deletion; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D009218:Myosins; D020691:rab GTP-Binding Proteins