Question

(1.5 pts.) Patients with Congenital Disorder of Glycosylation (for example, "CDG type Ia” or “CDG-Ia”), an inherited disease, can have a wide range of symptoms all caused by having mutations that affect the transfer of carbohydrates to proteins. Their inability to produce properly glycosylated proteins especially affects secreted proteins and those found on the cell surface. Deficiencies in these proteins lead to mental retardation, seizures, and liver disease. Which two organelles are most likely affected in these patients? Briefly explain why defects in these organelles would affect protein glycosylation.

Answer 1

Congenital Disorder of Glycosylation or CDG type Ia

This congenital disorder is due to mutation in the PMM2 gene. This gene is responsible for the production of the enzyme Phosphomannomutase 2. This enzyme is important in the process of glycosylation. It converts mannose - 6- phosphate to mannose - 1 - phosphate, which is a precursor of the GDP mannose. This further converted to mannose and these attach together to form an oligosaccharide chain which is then attached to a protein. This later forms the glycoprotein which are important integral membrane proteins.

Two organelles affected are endoplasmic reticulum (as the sugar building pathway occurs in this part of the cell) and golgi apparatus (remodeling of the sugar block happens here).

The mutation in PMM 2 gives rise to less mannose sugar resulting in absence of glycan chains in the protein which leads to the symptoms seen in the patients affected. Incorrect oligosaccharides too are produced which attach to proteins. N glycans are formed in the ER while O- glycosylation defects takes place in Golgi. N glycans are attached to asparagine while O glycans are attached to serine or threonine. N linked glycans help in formation of cell structures and also cell signalling. They are integral for immune system. O- Glycosylation is also important for immune system cell trafficking and other functions like tendon and cartilage flexibility. Mucins are O - glycosylated proteins which line the gastrointestinal tract. These are just few examples of the importance of glycosylation.

Glycosylation pathways happens in all the organ systems so this affects most organs, leading to multi systemic severe disease.