Chemistry Reference
In-Depth Information
by a multiprotein complex containing the PIGA, PIGC, PIGH and PIGQ sub-
units. The systemic loss of the GPI anchor is not compatible with life, but a GPI
anchor defi ciency limited to hematopoietic cells has been associated with a form
of hemolytic anemia called paroxysmal nocturnal hemoglobinuria (PNH, OMIM
311770) [8]. This complex and somewhat intimidating name indicates that the
affected patients notice dark-colored urine in the morning after sleep. Red blood
cells lacking GPI-anchored proteins are sensitive to complement-mediated lysis,
thus explaining the hemolysis and the accumulation of hemoglobin in the urine.
PNH is an acquired genetic disease mainly caused by mutation in the X- linked
PIGA
gene arising in hemopoietic stem cell clones. PNH patients are usually
diagnosed at about 40 years of age. The disease also features an increased inci-
dence of leukemia and increased thrombotic episodes. These complications
usually lead to the death of the patients within 10-20 years after diagnosis. Platelet
transfusion and anticoagulant therapies are commonly used to improve the
survival rate.
22.6
Defects Affecting Multiple Classes of Glycosylation
Defects of nucleotide-sugar biosynthesis and transport affect multiple classes of
glycosylation. Accordingly, the phenotypes of such defects are expected to be
severe considering the multiple biological processes are involved. Two nucleotide-
sugar transporter defects have been identifi ed to date in humans. Mutations in
the Golgi GDP-Fuc transporter gene have been found to cause a defi ciency of
protein fucosylation (CDG- IIc/LAD - II) [9] . In fact, CDG - IIc/LAD - II patients
present with recurrent infections and increased levels of circulating granulocytes
due to the defective traffi cking of leukocytes outside of the blood stream. The
fucosylation defect does not only affect leukocyte functions, since psychomotor
retardation, short stature and mild dysmorphism are also encountered in the
affected patients. It is presently unclear whether
O
- fucosylation is also impaired
in CDG-IIc/LAD-II. However, the absence of severe skeletal deformity, as seen in
the Lunatic Fringe defect (see Section 22.5), would suggest that the ER- localized
O
-fucosylation is not affected by the Golgi GDP-Fuc transporter defect. As the
mutations detected in CDG-IIc/LAD-II do not completely inactivate the trans-
porter activity, the fucosylation disorder can be successfully corrected by dietary
supplementation with fucose. This treatment has been shown to reduce the occur-
rence of infections and lead to a normalization of blood leukocyte levels in the
patients.
Mutations in the CMP-Sia transporter have been found in an infant presenting
with a severe bleeding disorder, characterized by decreased blood platelet and
neutrophil levels (CDG-IIf ). The CMP-Sia transporter defect leads to an apparent
loss of protein sialylation on hematopoietic cells, while several serum proteins,
like transferrin, were surprisingly unaffected. Furthermore, the impact of the
CMP-Sia transporter defect on ganglioside biosynthesis remains unknown. The
