Ras-associated binding (Rab)
proteins and Rab-associated
proteins are key regulators of vesicle transport, which is essential for the delivery of
proteins to specific intracellular locations. More than 60 human Rab
proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated
proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab
proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated
protein is expressed, frequent features are
hypopigmentation (Griscelli syndrome), eye defects (
Choroideremia,
Warburg Micro syndrome and
Martsolf syndrome), disturbed immune function (Griscelli syndrome and
Charcot-Marie-Tooth disease) and neurological dysfunction (X-linked non-specific
mental retardation,
Charcot-Marie-Tooth disease,
Warburg Micro syndrome and
Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as
infectious diseases and
type 2 diabetes. Rab
proteins must not only be bound to
GTP, but they need also to be 'prenylated'-i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of
cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as
statins, which inhibit isoprenylation, or biphosphonates, which inhibit that
farnesyl pyrophosphate synthase necessary for
Rab GTPase activity.
CONCLUSION: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.