Chemistry Reference
In-Depth Information
meaning that the identity of the proteins requiring glucosylated
O
- Fuc glycans
is still unknown.
The detection of
O
-Fuc glycans relies on complex analytic methods based on
liquid chromatography and mass spectrometry, which are only available in special-
ized research laboratories. So far only a few proteins, like the complement protein
properdin, have been shown to be aberrantly
O
- fucosylated in Peters - Plus patients,
and no biochemical analysis has been undertaken yet to quantify the glycosylation
defect found in Lunatic Fringe- associated spondylocostal dysostosis.
22.3
Glycosaminoglycans
The functional investigation of glycosaminoglycan ( GAG ) chains in model organ-
isms has demonstrated the importance of these glycans in the localization and
activation of various proteins (please see Chapter 11.1 structural aspects). There-
fore, it is somehow surprising that only few diseases of GAG chain assembly have
been documented so far. The main disorder related to GAG chain defects is mul-
tiple hereditary exostoses (OMIM 133700) - an autosomal dominant disease caused
by mutations in the
EXT1
and
EXT2
genes [6]. Exostoses represent protrusions of
bone material mainly occurring on long bones and originating from benign carti-
laginous tumors. Exostoses are quite frequent with an estimated prevalence of
1 : 50 000 in most ethnic groups. The
EXT1
and
EXT2
genes encode glycosyltrans-
ferases building heterodimers that catalyze the polymerization of heparan sulfate
(HS) chains. The inclusion of a mutant EXT1 or EXT2 subunit to the heterodimer
inactivates the enzyme, thereby explaining the dominant- negative effect. Theoreti-
cally, this situation causes a decreased enzymatic activity to 50% of normal levels.
This decreased activity leads to a signifi cant reduction of HS chain formation in
tissues, in which the amount of such GAG chains is tightly regulated. This is the
case for bone tissue, where HS chains are required for the proper localization of
various factors regulating endochondral ossifi cation, a process characterized by a
directional sequence of chondrocyte proliferation and differentiation (Figure 22.5).
Notably, the complete loss of the EXT activity is not compatible with life, explain-
ing why homozygous or combined heterozygous mutations in the
EXT
genes have
not been reported. Exostoses can transform, with a frequency of about 5%, into
malignant chondrosarcomas. This increased predisposition to cancer accounts for
the designation of
EXT1
and
EXT2
as tumor suppressor genes (for phenotype of
KO mice, please see Table 23.1 ).
Another defect of GAG chain biosynthesis is caused by mutations in the xylosyl-
protein
1,4 - Gal - transferase
XGPT1
, which catalyzes the transfer of the fi rst Gal
residue of the GAG core tetrasaccharide GlcA
β
1 - O)Ser
(please see Chapter 11.1). The resulting disease, which is called the progeroid form
of the Ehlers-Danlos syndrome (OMIM 130070), is characterized by mental retar-
dation, short stature and connective tissues abnormalities, such as loose skin,
wrinkled facies, osteopenia and joint hypermobility. The disease is very rare and
β
1,3Gal
β
1,3Gal
β
1,4Xyl(
β
