(mentions CMT) Rab proteins and Rab-associated proteins: major actors in the mec

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Eur J Pediatr. 2008 May 8

Rab proteins and Rab-associated proteins: major actors in the

mechanism of protein-trafficking disorders.

Corbeel L, Freson K.

Department of Pediatrics, University Hospital, Herestraat 49, 3000,

Leuven, Belgium

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.