Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding.

Valentina Cetica, Yvonne Hackmann, Samantha Grieve, Elena Sieni, Benedetta Ciambotti, Maria Luisa Coniglio, Daniela Pende, Kimberly Gilmour, Paolo Romagnoli, Gillian M Griffiths, Maurizio Aricò

Journal: The Journal of allergy and clinical immunology 2015;135(5):1310-8.e1

PMID: 25312756

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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.

Address: Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children's Hospital, Florence, Italy.; Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, United Kingdom.; Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.; Immunology, Great Ormond Street Hospital, London, United Kingdom.; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.; Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, United Kingdom. Electronic address: [email protected].; Pediatric Oncology Network, Istituto Toscano Tumori (I.T.T.), Florence, Italy. Electronic address: [email protected].

DOI: 10.1016/j.jaci.2014.08.039

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MeSH Terms: Adaptor Proteins, Signal Transducing, Adolescent, Albinism, Case-Control Studies, Cell Degranulation, Cell Line, Child, Child, Preschool, Cohort Studies, Cytotoxicity, Immunologic, DNA Mutational Analysis, Female, Gene Expression, Genetic Markers, Humans, Infant, Lymphohistiocytosis, Hemophagocytic, Male, Membrane Proteins, Models, Molecular, Mutation, Perforin, Phenotype, Protein Binding, Protein Conformation, Skin Pigmentation, rab GTP-Binding Proteins, rab27 GTP-Binding Proteins