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Juhi AroraMSc (F)

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Mutations often lead to protein misfolding and aggregation usually in the ER.

As a result, protein cannot be transported to the destined location.

Altered protein modifications may also lead to mislocalisation.

This review discusses the mutations in genes directly responsible for protein trafficking and the resulting diseases.

Vesicular transport is a process by which membrane bound vesicles are released from the donor compartment and travel to a specific cellular location.

Two major routes: Biosynthetic (or secretory) & Endocytic pathway.

In polarised cells, regulation of both biosynthetic and secretory pathways is tightly controlled.

Choice of trafficking pathway is governed by: Cell type, Cargo protein type, modification status and ligand.

Background

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Inherited Disorders of

Vesicular Trafficking machinery

(IDT)

Defects in Rab

and other GTPases

Abnormalities in

cytoskeleton and

associated proteins

Disorders of Cargo

recruitment and Vesicle

Biogenesis

Defects in

Vesicular Tetherin

g and Fusion

Common Symptoms: Hypopigmentation, disturbed cell mediated immune response and neurological

abnormalities

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Cargo proteins are recruited with the help of ligands and receptors at the point of vesicle assembly.

FV and FVIII both are required for efficient functioning of blood clotting system.

Symptoms: Moderate bleeding tendency

Cause: Mutations in ERGIC-53 or Multiple coagulation factor deficiency 2 (MCFD2) genes.

Type: Autosomal recessive Cytosolic MCFD2 recruits FV and

FVIII and forms a complex with ERGIC-53 to transport these factors in COP-II coated vesicles.

Disorders of Cargo Recruitment and Vesicle Biogenesis: Factor V and Factor VIII

coagulation factor deficiency

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Rab3A is the most abundantly expressed Rab protein in the brain. Present in all synapses and involved in Ca2+ mediated NT release. WMS is characterised by developmental defects of the eye, brain

and microgenitalia. Symptoms: Abnormally small eyes, small cornea, congenital

cataract, degeneration of optic nerve, Atonic pupils (large pupils with poor reflexes), intellectual disability, developmental delays in brain, growth failure, underdevelopment of reproductive organs etc

Defects in Rab and Rab-associated proteins:Warburg Micro Syndrome (WMS)

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Type: Autosomal Recessive Cause: Mutation in Rab3GAP. Rab3GAP converts Rab3GTP to inactive Rab3GDP and thus may

determine the timing of dissociation of Rab3a from synaptic vesicles. Abnormal vesicular secretion of neurotransmitters and or hormones

produced by hypothalmic/pitutary axis Rab3GAP knockout mice accumulated Rab3GTP resulting in

inhibition of Ca2+ dependant release of glutamate from cerebrocortical synaptosomes.

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Many vesicles are guided to their location by cytoskeletal elements such as microtubules.

Microtubules are polymers composed of α and β tubulin with a peripheral fast growing ‘+’ end and a slow growing, centrally located ‘-’ end.

HSPs are a group of disorders linked to abnormal cytoskeleton-associated trafficking and characterised by progressive lower limb spasticity and weakness.

Abnormalities in cytoskeleton and associated proteins: Hereditary spastic paraplegias (HSPs)

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Degeneration of the ends of the corticospinal tracts within the spinal cord.

Symptoms: Spasticity, weakness in lower limbs, epilepsy, ataxia, mental retardation, deafness, dementia, optic neuropathy etc.

Type: Autosomal dominant, recessive or X-linked. Cause: Mutation in SP4 gene encoding for spastin. Spastin is an ATPase with an N terminal Microtubule Interacting

and Trafficking (MIT) domain. Its function in microtubule remodelling appears to be crucial for axonal maintenance.

It binds to CHMP1b protein associated with ESCRTIII complex (endosomal sorting complex required for transport). It is thought to be responsible for the final sorting and concentration of cargo to a subset of multivesicular body membranes.

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Few genetic conditions have been recognised to result from mutations in genes encoding known SNARE proteins.

CEDNIK syndrome is a neurocutaneaous syndrome characterized by severe developmental abnormalities of the nervous system and aberrant differentiation of the epidermis.

Symptoms: cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma, severe neurological impairment, abnormality of eye movement.

Type: Autosomal Recessive

Defects in Vesicular Tethering and Fusion:CEDNIK

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Cause: Homozygous mutation in SNAP29 gene that encodes for SNARE protein 29.

SNAP29 is found to mediate intracellular trafficking. It localises to intracellular membrane structures. It may have a role in intracellular trafficking of IGF-1 and other proteins in neuroectodermal tissues.

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