Evidence for defective Rab GTPase-dependent cargo traffic in immune disorders.
A fully functional immune system is essential to protect the body against pathogens and other diseases, including cancer. Vesicular trafficking provides the correct localization of proteins within all cell types, but this process is most exquisitely controlled and coordinated in immune cells because of their specialized organelles and their requirement to respond to selected stimuli. More than 60 Rab GTPases play important roles in protein trafficking, but only five Rab-encoding genes have been associated with inherited human disorders, and only one of these (Rab27a) causes an immune defect. Mutations in RAB27A cause Griscelli Syndrome type 2 (GS2), an autosomal recessive disorder of pigmentation and severe immune deficiency. In lymphocytes, Munc13-4 is an effector of Rab27a, and mutations in the gene encoding this protein (UNC13D) cause Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL3). The immunological features of GS2 and FHL3 include neutropenia, thrombocytopenia, and immunodeficiency due to impaired function of cytotoxic lymphocytes. The small number of disorders caused by mutations in genes encoding Rabs could be due to their essential functions, where defects in these genes could be lethal. However, with the increasing use of next generation sequencing technologies, more mutations in genes encoding Rabs may be identified in the near future.
['Krzewski|Konrad|K|', 'Cullinane|Andrew R|AR|']
D002609:Chediak-Higashi Syndrome D003424:Crohn Disease D005786:Gene Expression Regulation D022861:Hermanski-Pudlak Syndrome D006801:Humans D007153:Immunologic Deficiency Syndromes D051359:Lymphohistiocytosis, Hemophagocytic D008565:Membrane Proteins D009154:Mutation D016116:Piebaldism D000081207:Primary Immunodeficiency Diseases D021381:Protein Transport D015398:Signal Transduction D013602:T-Lymphocytes, Cytotoxic D022161:Transport Vesicles D020691:rab GTP-Binding Proteins D000075745:rab27 GTP-Binding Proteins
Rab GTPases Rab27a Griscelli Syndrome Type 2 Familial Hemophagocytic Lymphohistiocytosis Type 3 Immunodeficiencies Muc13-4