Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding.
Authors
Cetica, Valentina
Hackmann, Yvonne
Grieve, Samantha
Sieni, Elena
Ciambotti, Benedetta
Coniglio, Maria Luisa
Pende, Daniela
Gilmour, Kimberly
Romagnoli, Paolo
Aricò, Maurizio
Publication Date
2015-05Journal Title
J Allergy Clin Immunol
ISSN
0091-6749
Publisher
Elsevier BV
Volume
135
Issue
5
Pages
1310-8.e1
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Cetica, V., Hackmann, Y., Grieve, S., Sieni, E., Ciambotti, B., Coniglio, M. L., Pende, D., et al. (2015). Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding.. J Allergy Clin Immunol, 135 (5), 1310-8.e1. https://doi.org/10.1016/j.jaci.2014.08.039
Abstract
BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and often fatal disorder characterized by defective cellular cytotoxicity and hyperinflammation, and the only cure known to date is hematopoietic stem cell transplantation. Mutations in RAB27A, LYST, and AP3B1 give rise to FHL associated with oculocutaneous albinism, and patients with FHL are usually only screened for mutations in these genes when albinism is observed. A number of patients with FHL and normal pigmentation remain without a genetic diagnosis. OBJECTIVE: We asked whether patients with FHL with immunodeficiency but with normal pigmentation might sometimes have mutations that affected cellular cytotoxicity without affecting pigmentation. METHODS: We carried out mutation analysis of RAB27A, LYST, and AP3B1 in patients with FHL with pigment dilution, as well as a cohort with no clinical evidence of pigment dilution but no mutations in the other known FHL-related genes (PRF1, STXBP2, and UNC13D). RESULTS: We identify patients with Griscelli syndrome type 2 with biallelic mutations in RAB27A in the absence of albinism. All 6 patients carried mutations at amino acids R141, Y159, or S163 of Rab27a that disrupt the interaction of Rab27a with Munc13-4, without impairing the interaction between melanophilin and Rab27a. CONCLUSION: These studies highlight the need for RAB27A sequencing in patients with FHL with normal pigmentation and identify a critical binding site for Munc13-4 on Rab27a, revealing the molecular basis of this interaction.
Keywords
Cell Line, Humans, Albinism, rab GTP-Binding Proteins, Adaptor Proteins, Signal Transducing, Membrane Proteins, Genetic Markers, Skin Pigmentation, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, Cell Degranulation, Cytotoxicity, Immunologic, Gene Expression, Protein Conformation, Protein Binding, Phenotype, Mutation, Models, Molecular, Adolescent, Child, Child, Preschool, Infant, Female, Male, Lymphohistiocytosis, Hemophagocytic, Perforin, rab27 GTP-Binding Proteins
Sponsorship
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (103930/Z/14/Z)
Wellcome Trust (75880)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1016/j.jaci.2014.08.039
This record's URL: https://www.repository.cam.ac.uk/handle/1810/276578
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