When intracellular logistics fails - genetic defects in membrane trafficking

Abstract

The number of human genetic disorders shown to be due to defects in membrane trafficking has greatly increased during the past five years. Defects have been identified in components involved in sorting of cargo into transport carriers, vesicle budding and scission, movement of vesicles along cytoskeletal tracks, as well as in vesicle tethering, docking and fusion at the target membrane. The nervous system is extremely sensitive to such disturbances of the membrane trafficking machinery, and the majority of these disorders display neurological defects - particularly diseases affecting the motility of transport carriers along cytoskeletal tracks. In several disorders, defects in a component that represents a fundamental part of the trafficking machinery fail to cause global transport defects but result in symptoms limited to specific cell types and transport events; this apparently reflects the redundancy of the transport apparatus. In groups of closely related diseases such as Hermansky-Pudlak and Griscelli syndromes, identification of the underlying gene defects has revealed groups of genes in which mutations lead to similar phenotypic consequences. New functionally linked trafficking components and regulatory mechanisms have thus been discovered. Studies of the gene defects in trafficking disorders therefore not only open avenues for new therapeutic approaches but also significantly contribute to our knowledge of the fundamental mechanisms of intracellular membrane transport.

Sculpting the endomembrane system in deep time: High resolution phylogenetics of Rab GTPases

“…The endomembrane system consists of many discrete, interconnected compartments with distinct protein and lipid compositions, morphologies and functions that enable the uptake (endocytosis) and export (exocytosis) of macromolecules, particles and other metabolites. Numerous pathological conditions are associated with defects in endomembrane activity (Huizing et al, 2008;Olkkonen and Ikonen, 2006).…”

Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure

“…HLH has been characterized by an unremitting polyclonal CD8 + T-cell expansion, and lymphocytic infiltration of visceral tissues that leads to macrophage activation (hemophagocytosis) and the deleterious release of several cytokines, including interferon γ, interleukins (IL-1, IL-6, IL-18) and tumor necrosis factor-α, which sustains the macrophage activation and leads to hyperinflammation, involving progressive deterioration of the central nervous system, and multiple organ failure (10)(11)(12)(13). RAB27A gene encodes the small GTPase protein Rab27a, which is required for peripheral anchorage of melanosomes in melanocytes, as well as exocytosis of cytolytic granules in cytotoxic T lymphocytes and natural killer cells or secretory vesicles in endocrine cells (11,12,(14)(15)(16)(17).…”

Trafficking Guidance Receptors

“…To carry out their essential activities, however, guidance receptors must be localized correctly to axons or dendrites (Allen and Chilton, 2009), and the mechanisms controlling the polarized traffic of these receptors are crucial to the proper wiring of neuronal circuits. In other polarized cell types, defects in polarized receptor traffic cause a variety of pathologies; one can expect the same in the nervous system (Olkkonen and Ikonen 2006).…”