Chemistry Reference
In-Depth Information
description of additional cases encompassing additional mutations is required to
better defi ne the scope of organ functions and processes altered by reduced
sialylation.
The defect of CMP-Sia transport demonstrates the importance of sialylation in
human physiology. Accordingly, defects of Sia or CMP-Sia biosynthesis would also
be expected to cause severe bleeding disorders and probably other organ dysfunc-
tions. The UDP - GlcNAc 2 - epimerase/
N
- acetylmannosamine kinase ( GNE ) protein
is rate limiting in the synthesis of Sia. Accordingly, GNE activity also correlates
with the level of sialylation on hematopoietic cells. Therefore, the association of
GNE mutations to a mild form of a neuromuscular disorder called hereditary
inclusion body myopathy (IBM, OMIM 600737) came as a surprise. IBM is char-
acterized by a late-onset myopathy mostly limited to leg muscles. Histological
examination of IBM tissue reveals typical intramuscular vacuoles and fi lamentous
inclusions of unknown origin. Glycan analysis of IBM muscle biopsies revealed
decreased levels of sialylated
O
-glycans, whereas sialylation of
N
- glycans remained
unchanged. The rather weak phenotype of GNE defi ciency raises several questions
concerning the activity of possible salvage pathways that could compensate for the
loss of endogenous Sia biosynthesis. However, the targeted disruption of the
GNE
gene in mice leads to embryonic lethality, suggesting that salvage pathways cannot
fully compensate for the loss of the GNE activity. Additional work is required to
understand the relationship between the pathogenesis of IBM, the level of residual
GNE activity and the contribution of alternate sources of Sia. Interestingly, GNE
mutations in the allosteric site of the epimerase domain cause another disease,
sialuria (OMIM 269921), a dominant inherited disorder characterized by increased
cellular and urinary Sia levels.
Other defects of sugar metabolism, such as galactosemia (OMIM 230400) and
fructosemia (OMIM 229600), lead to limited availability of specifi c nucleotide
sugars and thus to abnormal glycosylation. However, because these defects impair
several pathways linked to the energy metabolism, they are not considered as true
diseases of glycosylation and are therefore not discussed here.
22.7
Traffi cking Disorders
Proper glycosylation not only requires adequate donor substrates and enzyme
levels, the latter must also be correctly localized along the secretion pathway. The
localization of glycosylation reactions is a dynamic process that is tightly regulated
together with the fl ow of secreted proteins and the shaping of the ER, ER- Golgi
intermediate compartment and Golgi apparatus. Recently, defects of glycosylation
have been related to the abnormal assembly of the COG complex, which is part
of the vesicular transport machinery. COG, which stands for ' conserved oligomeric
Golgi', is a complex of eight subunits found in eukaryotes from yeast up to human
cells [10]. Although the functions of COG are still being investigated, it is clear
that COG is required for the retrograde transport of glycosyltransferases between
