Protein Glycosylation: Implications for In Vivo Functions and Therapeutic Applications - Advances in Biochemical Engineering Biotechnology - page 174

4.1
Carbohydrate Deficient Glycoprotein Syndrome (CDGS)

Persons with CDGS exhibit abnormal glycosylation of several serum glyco-
proteins ( -1 antitrypsin, transferrin). It is a hereditary multisystemic glycosy-

lation disorder with involvement of the central and peripheral nervous system
leading to mental retardation and hypotonia [149]. This appears to be a highly
substrate specific defect [150]. The deficiency of SA results in the presence of
abnormal isoforms. Glycoprotein transport along the secretory pathway is
delayed and dilation of ER indicates a retention of misfolded glycoproteins.
Alternatively,CDGS could be due to defective synthesis and transfer of dolichol-
linked precursors [151].The disease is usually diagnosed by isoelectric focusing
(IEF) of the proteins.

a

4.2
Cystic Fibrosis

A number of mutations have been found to exert their effect by specific change
in a particular protein leading to altered protein folding and defective modi-
fication. Some of the human diseases for which altered protein folding and
inability of the mutant protein to achieve its functional conformations are
responsible include cystic fibrosis (CF) and maple syrup urine disease [152].
Cystic fibrosis is one of the most frequent inherited lethal disorders in humans
and is caused by the functional absence of a plasma membrane Cl channel,
designated cystic fibrosis transmembrane conductance regulator (CFTR) [153].
Clinical symptoms include both pancreatic and pulmonary insufficiencies. The
vast majority of severe CF cases are linked to a single genetic lesion, deletion of
a Phe codon ( F508).This interferes with the folding of newly synthesized CFTR

polypeptides and leads to incomplete N -glycosylation, failure to traffic to the
plasma membrane, and retention and degradation by the ER quality control
mechanism.

D

4.3
Amyloid Diseases

Amyloidosis is a group of diverse conditions in which one of the 16 normally
soluble and functional proteins self-assembles into an insoluble protease
resistant

-sheet fibril form. The insoluble fibril associates with plasma and
extracellular matrix proteins and proteoglycans to form neurotoxic amyloid
deposits as in Alzheimer's disease [154]. It is a progressive neurodegenerative
disorder of the aged and characterized by a series of structural abnormalities
in the brain, including dense extracellular aggregates called senile plaques.
The major component of senile plaque is a hydrophobic 39-43 amino acid
peptide termed the

b

b -amyloid peptide (A b ), proteolytically derived from a

larger membrane-spanning glycoprotein, b -amyloid precursor protein ( b PP).