Chemistry Reference
In-Depth Information
defi ciency so that these disorders of vesicular transport should not count solely as
diseases of glycosylation.
The severity of
N
-glycosylation disorders largely depends on the genes affected
and on the degree of inactivation achieved by the underlying mutations. Most types
of CDG are associated with symptoms such as psychomotor retardation, dysmor-
phic features, hypotonia, cerebellar hypoplasia, hormonal disorders, coagulopa-
thies and stroke-like episodes. By contrast, defi ciency of phosphomannose
isomerase, known as CDG-Ib (OMIM 602579), is associated with normal psycho-
motor development, but presents with hypoglycemia, vomiting and diarrhea. Defi -
ciency of the GDP-Fuc transporter (CDG-IIc) has also been called leukocyte
adhesion defi ciency (LAD)-II, because the lack of fucosylated glycans impairs leu-
kocyte rolling mediated by P-, E- and L-selectins (see Chapters 19 and 27). Conse-
quently, CDG-IIc/LAD-II patients are immune compromised and thereby prone
to infections. Defi ciency of the CMP-Sia transporter, assigned as CDG-IIf, affects
the sialylation of many glycans classes. The single CDG-IIf patient described to
date died a few months after birth of severe bleeding related to a blood platelet
disorder. It is unclear whether other organ functions were affected by the general-
ized sialylation defi ciency.
Unfortunately, successful therapies are limited to CDG- Ib and CDG - IIc/LAD - II,
which can be corrected by oral supplementation with mannose and fucose, respec-
tively (please see Info Box 2). Other forms of CDG are insensitive to carbohydrate
supplementation. Various derivatives of sugar metabolites like mannose-1-phos-
phate have been tested in cell culture with little success. Such approaches are
questionable since manipulation of sugar-phosphate levels can have drastic effects
on glycolysis and on the cellular ATP pool.
22.2
O
- Glycosylation
Some forms of
O
-glycosylation occur nearly on any kind of glycoproteins (for
details, please see Chapter 7). This is the case for mucin-type
O
- GalNAc glycosyl-
ation. By contrast,
O
- Man and
O
-Fuc glycans are mainly limited to few classes of
glycoproteins. Accordingly, defects in the assembly of
O
- GalNAc,
O
- Man and
O
-
Fuc glycans impair distinct biological processes and hence cause different types
of diseases.
22.2.1
O
- G al NA c Glycosylation
As discussed in Chapter 7 ,
O
-GalNAc glycosylation is initiated by a family of more
than 15 polypeptide GalNAc-transferase enzymes. The various polypeptide
GalNAc-transferase isoforms show varying degrees of acceptor substrate specifi c-
ity and the level of redundancy between these isoforms makes it diffi cult to predict
the pathological outcome of a given enzyme defi ciency. Probably for this reason,
