A novel Rab27a mutation binds melanophilin, but not Munc13-4, causing immunodeficiency without albinism

• Published in: Journal of allergy and clinical immunology 2016-08, Vol.138 (2), p.599-601.e3
• Main Authors: Netter, Petra, PhD, Chan, Sanny K., MD, PhD, Banerjee, Pinaki P., PhD, Monaco-Shawver, Linda, BS, Noroski, Lenora M., MD, MPH, Hanson, Imelda C., MD, Forbes, Lisa R., MD, Mace, Emily M., PhD, Chinen, Javier, MD, PhD, Gaspar, H. Bobby, PhD, Sleiman, Patrick, PhD, Hakonarson, Hakon, MD, PhD, Klein, Christoph, MD, PhD, Ehlayel, Mohammad S., MD, Orange, Jordan S., MD, PhD
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adenoviruses; Albinism - genetics; Albinism - immunology; Albinism - metabolism; Allergy and Immunology; Amino Acid Substitution; Consanguinity; Cytotoxicity; Female; Genes, Recessive; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - metabolism; Immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymphocytes; Lymphohistiocytosis, Hemophagocytic - genetics; Lymphohistiocytosis, Hemophagocytic - immunology; Lymphohistiocytosis, Hemophagocytic - metabolism; Male; Membrane Proteins - metabolism; Mutation; Mutation, Missense; Patients; Pedigree; Piebaldism - genetics; Piebaldism - immunology; Piebaldism - metabolism; Pigments; Primary Immunodeficiency Diseases; Protein Binding - genetics; rab27 GTP-Binding Proteins - genetics; rab27 GTP-Binding Proteins - metabolism; Studies
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.12.1337

In melanocytes Rab27a interacts with melanophilin to mediate the melanosome transport required for pigmentation.1 In natural killer (NK) cells and cytotoxic T lymphocytes, degranulation and thereby cell-mediated cytotoxicity require interaction of the active form of Rab27a with Munc13-4.2,3 Mutations in the human RAB27A gene cause the autosomal recessive Griscelli syndrome type 2 (GS2) with diluted pigmentation and immunodeficiency, which can progress to hemophagocytic lymphohistiocytosis (HLH).4 Recently, 6 patients with GS2 and normal pigmentation have been reported, identifying Rab27a mutations that selectively disrupt Munc13-4 binding when re-expressed in HEK293 cells.5 Here we present a new case of GS2 with no dilution of pigmentation and extend prior biochemical results through physiologic cell expression studies. Using NK and melanoma cell lines, we have investigated the binding activity of the mutations to the endogenously expressed interaction partners in comparison with wild-type Rab27a. [...]we confirm the previously described biology in a truly physiologic context using cells that have full ability to mediate the functions of cytotoxicity or pigmentation.