Transcript Lectures 1 and 2 - University of California, San Diego

Essentials of Glycobiology
Lecture 36
Ajit Varki
Changes in Glycosylation in Systemic Diseases
(other than Cancer)
Changes in Glycosylation in Systemic Diseases
 CARDIOVASCULAR MEDICINE
 DERMATOLOGY
 ENDOCRINOLOGY AND METABOLISM
 GASTROENTEROLOGY
 HEMATOLOGY
 IMMUNOLOGY AND RHEUMATOLOGY
 INFECTIOUS DISEASE
 NEUROLOGY AND PSYCHIATRY
 PULMONARY MEDICINE
 ONCOLOGY (already covered in lecture 35)
Cardiovascular Medicine
Role of Selectins in Reperfusion Injury
Role of Selectins, Glycosaminoglycans and
Sialic Acids in Atherosclerosis
EXIT OF WHITE BLOOD CELLS FROM THE CIRCULATION
INTO TISSUES INVOLVES SELECTINS
SELECTINS
P-SELECTIN
Platelets
ACTIVATION
White
cell
Blood vessel wall
INFLAMMATION
INJURY
EARLY PHASES OF BLOOD VESSEL INJURY RESPONSE
ALSO INVOLVES SELECTINS
Cardiovascular Medicine
Role of Selectins in Reperfusion Injury
 Many cardiovascular disorders (stroke, myocardial infarction,
hypovolemic shock, etc.) characterized by period of decreased/absent
blood flow, followed by re-perfusion (natural or therapeutic).
 Despite tissue rescue from anoxemic necrosis, entry of leukocytes into
reperfused area results in tissue damage.
 P-selectin on activated endothelium in reperfused area and L-selectin
on leukocytes play a key role in mediating initial steps of this cascade
 Substantial data in animal models indicates that blockade of initial
selectin-based recognition can ameliorate subsequent tissue damage.
 Therapeutic potential in humans is likely, but remains unrealized
Pathology of Atherosclerosis
Glycobiology of Atherosclerosis (Selectins)
 Earliest step in atherosclerosis involves entry of
monocytes into subendothelium via endothelial P-selectin
recognition of PSGL-1 ligand on circulating monocytes.
 Induction of endothelial P-selectin expression may result
from oxidized lipids that are present in low-density
lipoprotein (LDL) particles
 Atherosclerotic lesions in LDL Receptor-deficient mice
show delayed progression in a P-selectin deficient
background and even slower progression in combined Pand E-selectin deficiency.
 Therapeutic significance of the above facts are unexplored
Glycobiology of Atherosclerosis (Glycosaminoglycans)
 Subendothelial retention of LDLs in early atherosclerotic
plaque thought occur at least partly via interactions with
matrix proteoglycans.
 Interactions thought to cause irreversible structural
alterations of LDL, potentiating oxidation and uptake by
macrophages and smooth muscle cells.
 At molecular level, clusters of basic amino acids in Apo-B
(protein moiety of LDL) thought to bind negatively charged
GAG chains of proteoglycans.
 Some evidence for reduction of atherosclerosis in animals
with heparin treatment.
 Practical therapeutic significance in humans unknown.
Glycobiology of Atherosclerosis (Sialic Acids)
 Many reports of lowered sialylation of circulating LDL in patients with
coronary artery disease.
 Pathophysiological significance of this finding in unclear
 Mechanism(s) involved remain unclear. Recent paper claims a serum
LDL-associated trans-sialidase that transfers sialic acids from LDL to
other serum proteins!
 Pathological hypothesis is that the desialylated LDL is more prone to
be taken up and incorporated into atheromatous plaques.
 However, there are also some contradictory data in the literature
concerning this issue
 Practical therapeutic significance in humans unknown.
Dermatology
Role of Selectins in Inflammatory Skin Diseases
Dermatology
Role of Selectins in Inflammatory Skin Diseases
 Some inflammatory skin diseases (e.g., atopic dermatitis, contact dermatitis)
involve entry of T-helper (Th1) lymphocytes with a pathogenic role into dermis.
 Such skin lesions sometimes associated with persistent expression of Eand/or P-selectin on skin endothelial cells.
 E-selectin can recruit circulating Th1 lymphocytes carrying the Cutaneous
Lymphocyte Antigen - a specific E-selectin ligand epitope carried on a subset
of PSGL-1 molecules.
 P-selectin binding form of PSGL-1 is up-regulated in activated Th1 cells and
also serves to mediate exit.
 Consistent observations made in experimental models, including selectin and
selectin-ligand deficient animals
 Potential therapy in humans unexplored
Endocrinology and Metabolism
Non-enzymatic Glycation and Complications of Diabetes Mellitus
 Diabetes mellitus (DM) - dysregulated glucose metabolism resulting
from absolute (Type I) or relative (Type II) lack of insulin action
 Characteristic long-term vascular and neurologic complications are
the major causes of death
 High glucose in body fluids accelerates normal process in which openchain (aldehyde) form of glucose reacts with lysine residues on
proteins, giving reversible Schiff bases (non-enzymatic glucosylation).
 Adducts undergo irreversible Amadori rearrangement and "browning"
(Maillard) reactions, giving Advanced Glycation End products (AGE).
 Resulting protein cross links can affect cell functions, and AGE can is
recognized by some receptors (e.g., RAGE, macrophage scavenger
receptor, perhaps participating in acceleration of atherogenesis).
 Is this a normal process of aging accelerated in the setting of the
chronic persistent hyperglycemia of uncontrolled diabetes mellitus?
Endocrinology and Metabolism
Altered Glycosylation and Complications of Diabetes Mellitus
 Increased production of UDP-GlcNAc caused by the conversion of excess
glucose via the Glucosamine:Fructose Aminotransferase (GFAT pathway). One
hypothesis is that increased cytosolic UDP-GlcNAc gives rise to secondary
increase of O-linked-GlcNAc levels on nuclear and cytosolic glycoproteins.
GFAT
Endocrinology and Metabolism
Altered Glycosylation and Complications of Diabetes Mellitus
 Nephropathy - diabetic complication with high mortality. Begins with
microalbuminuria, progresses to nephrotic syndrome (macroalbuminuria) and
then decreased glomerular filtration rate - finally end-stage renal disease.
 Proteinuria correlated with reduction in heparan sulfate proteoglycan of
glomerular basement membrane.
 Underlying mechanism may involve reduction in HS synthesis by glomerular
epithelial cells, somehow caused by the high glucose in the environment.
 Decrease in anionic charge thought to affect porosity of the glomerular
basement membrane.
 N-deacetylase:N-sulfotransferase that plays a key role in heparan sulfate
biosynthesis has reduced activity in poorly regulated diabetic animals.
Gastroenterology
Infections and Ulcerative diseases of the GI tract
 Most gastrointestinal pathogens bind first to GI mucosal glycans. Changes in
mucosal glycosylation associated with age, genetic background and/or diet
may affect variation in susceptibility to certain infections.
 Ulcerative Colitis - non-infectious acquired disease with remitting and relapsing
segmental ulcerations of the colon.
 Primary pathogenetic mechanisms remain unknown
 Sialic acids of normal colon are heavily O-acetylated
 Loss of sialic acid O-acetylation is seen in Ulcerative Colitis, but it is not known if
this is cause or effect.
 The types of mucin molecules produced and their glycosylation can also be altered
in Ulcerative Colitis. Again, it is not known if this is cause or effect.
 Some evidence for selectin involvement in leukocyte flux into colonic mucosa
(beneficial effects of heparin reported!)
Immunology and Rheumatology
Changes in Immunoglobulin G Glycosylation in Rheumatoid Arthritis(RA).
 N-glycans in constant (CH2 or Fc) region of human IgG are buried
between the folds of the two constant regions.
 Chains often immobilized by carbohydrate-protein interactions which
can be seen in crystal structure (glycans typically invisible in crystals).
Immunology and Rheumatology
Changes in Immunoglobulin G Glycosylation in Rheumatoid Arthritis(RA).
 Biantennary complex type N-glycans of IgG hardly ever completed into
fully sialylated molecules. Most molecules remain with one or more
terminal beta-linked Gal residues (so-called G1 and G2 molecules).
 In Rheumatoid Arthritis, major fraction of glycans on serum IgG
molecules have decreased galactosylation, some carrying no galactose
at all (so-called Go molecules).
 Severity of disease correlates with % Go, and spontaneous
improvement during pregnancy correlates with increases in G1 and G2.
 Hypothesis: Fc N-glycans maintain conformation of Fc domains as well
as the hinge regions - necessary for effector functions e.g.,
complement binding and antibody-dependent cytotoxicity.
Immunology and Rheumatology
Changes in Immunoglobulin G Glycosylation in Rheumatoid Arthritis(RA).
 NMR studies indicate G0 glycans have increased mobility
resulting from loss of interactions with Fc protein. Regions
of protein surface normally covered by glycans may be
exposed in RA.
 Some studies suggest that the more mobile G0 glycans are
recognized by circulating mannose binding protein,
activating complement directly.
 RA also characterized by immune complexes consisting of
antibodies (rheumatoid factor) directed against Fc region of
other IgG molecules.
Immunology and Rheumatology
Changes in Immunoglobulin G Glycosylation in Rheumatoid Arthritis(RA).
 Lowered activities of beta-galactosyltransferase reported in
lymphocytes from patients with RA.
 However, appearance of Go molecules is a general feature
of other unrelated chronic granulomatous diseases as well
as osteoarthritis (non-autoimmune arthritis of the elderly)
 Change in IgG glycosylation in RA remains an interesting
phenomenon whose significance and pathogenic role have
yet to be defined.
 Regardless, it may be of diagnostic and prognostic value.
Immunology and Rheumatology
Changes in the O-glycans of CD43 in Wiskott-Aldrich Syndrome.
 Inherited disease with skin eczema, altered cellular immune response
and low platelet counts
 Early studies suggested absence of CD43 (leukosialin) the major Oglycosylated cell surface protein of leukocytes.
 Polypeptide is actually expressed normally, but has slower gel mobility
because of increased branching of O-glycans.
 Recent data indicate that the primary defect is not in glycosylation, but
in a transcription factor.
 However, glycan changes seen in resting T cells are same as those that
are induced by activation of normal T cells.
 Remains possible that some aspects of the immune disorders are due
to a secondary change in glycosylation
Immunology and Rheumatology
Changes in the O-glycans of CD43 in Wiskott-Aldrich Syndrome.
Infectious Disease
Glycan Recognition by Bacterial Adhesins, Toxins & Viral Hemagglutinins.
Desialylation of Blood Cells by Microbial Sialidases During Infections.
 Several microbes produce sialidases (neuraminidases) that are
“virulence factors” in pathogenesis of diseases that they cause.
 In some severe infections, e.g. Clostridium perfringens gas gangrene,
sialidase can appear in the plasma.
 Circulating blood cells and proteins can become desialylated, giving
enhanced clearance and anemia.
 Detection of the circulating sialidase has been proposed to have
diagnostic and prognostic significance.
 Whether inhibiting the sialidase with appropriate inhibitors will have a
therapeutic value has not been investigated.
Nephrology
Loss of Glomerular Sialic Acids in Nephrotic Syndromes
 Nephrotic syndrome - kidney glomerulus fails to retain serum proteins
during filtration, allowing spill into urine.
 The mucin podocalyxin on foot processes (pedicles) of glomerular
podocytes helps maintain pore integrity - excludes large proteins from
filtrate.
 Sialic acid residues of podocalyxin critical in this process.
 Loss of glomerular sialic acid in "minimal change renal disease" and in
nephrotic syndrome following infections.
 Proteinuria and renal failure after inoculation of sialidase in rats - loss
of glomerular sialic acids and effacement of foot processes.
 Aminonucleoside nephrosis in rats by Puromycin injection. Defective
sialylation of podocalyxin and glomerular glycosphingolipids detected.
Nephrology
Changes in IgA O-glycans in IgA Nephropathy
 Non-immunologic glomerular accumulation of aggregated IgA1, with
resulting damage and nephrotic syndrome.
 O-glycans on serum IgA are truncated.
 O-glycans may stabilize tertiary structure of IgA. Studies of heatinduced aggregation indicate that altered O-glycans on hinge region
gives a loss of conformational stiffness.
 Removal of O-glycans from IgA1 gives noncovalent self-aggregation
and a increased adhesion to ECM proteins.
 Underglycosylation of the IgAl molecule found in IgA nephropathy is
likely to be involved in the pathogenesis.
 Primary mechanisms causing the underglycosylation remain unknown
(Cosmc defect causing decreased Core 1 production?)
Neurology and Psychiatry
Pathogenic Autoimmune Antibodies Directed Against Neuronal Glycans
 Diseases associated with circulating antibodies against glycans
enriched in nervous system - autoimmune damage. Antibodies arise
via at least three distinct mechanisms.
 1. Benign or malignant B cell neoplasms (benign monoclonal
gammopathy of unknown significance - MGUS, Waldenstrom's
Macroglobulinemia, plasma cell myeloma) can secrete monoclonal IgM
or IgA specific for either ganglio-series gangliosides, or, sulfated
glucuronosyl glycans (“HNK-1 epitope”). Resulting demyelinating
peripheral neuropathy sometimes more damaging than primary
disease.
Therapy - try to treat primary disease with chemotherapy, or attempt
removal of immunoglobulin by plasmapheresis. Both approaches are
usually unsuccessful.
CHONDROITIN
HYALURONAN
Neural Glycosphingolipids
as Target Antigens
SULFATE
of Paraproteins
in
Monoclonal
Gammopathies
GLYCOSAMINOP
HEPARAN SULFATE
GLYCANS
S
S
S
S
S
Ser-O-
S
S
NS
NS
-O-Ser
Proteoglycan
N-LINKED CHAINS
Ac
O-LINKED
CHAIN
GLYCOPHOSPHOLIPID
ANCHOR
P
S
Etn
P
S
O
Ser/Thr
N
Asn
N
Asn
NH 2
INOSITOL
Glycoprotein
GLYCOSPHINGOLIPID
OUTSIDE
INSIDE
O-LINKED GlcNAc
O
Ser
P
S
Neurology and Psychiatry
Pathogenic Autoimmune Antibodies Directed Against Neuronal Glycans
 2. Immune reaction to molecular mimicry of ganglioside structures by
lipooligosaccharides (LOS) of bacteria like Campylobacter jejuni.
Following intestinal infection, circulating antibodies against
gangliosides appear. Associated with onset of demyelinating
neuropathy involving peripheral or central nervous systems:
Guillain-Barre syndrome or Miller-Fisher syndromes, respectively.
Therapy -support patient until antibody production fades. Potential for
active removal of antibodies to be explored.
 3. “Iatrogenic” disease arising from recent attempts to treat stroke
patients with intravenous bovine brain gangliosides. Some evidence
that treatment is beneficial for primary disease. However, several
cases of Guillain-Barre reported as a likely side-effect. Traces of
Neu5Gc in bovine gangliosides may play a role in enhancing immunity
Glycobiology of Alzheimer's Disease.
 Common primary degenerative dementia of humans with insidious
onset and progressive course. Ultimate diagnosis made by histological
examination of brain - characteristic amyloid plaques with
neurofibrillary tangles that are associated with neuronal death.
 Paired helical filaments are major component of neurofibrillary tanglescomposed of microtubule-associated protein tau. Tau is in a
hyperphosphorylated state and no longer binds microtubules - selfassembles to form the paired helical filaments.
 Normal brain tau is multiply modified by Ser(Thr)-O-linked GlcNAc.
Hypothesis: site-specific or stoichiometric changes in O-GlcNAc may
allow excessive phosphorylation, causing paired helical filaments.
Glycobiology of Alzheimer's Disease (continued).
 Hyperphosphorylated tau in Alzheimer's disease brain is found in association
with heparan sulphate proteoglycans.
 Non-phosphorylated tau isoforms with three microtubule-binding repeats form
paired helical-like filaments under physiological conditions in vitro, when
incubated with heparan sulphate. Heparin also prevents tau from binding to
microtubules and promotes microtubule disassembly.
 Heparin stimulates tau phosphorylation by protein kinases
 Thus, HS-GAGs may be a critical factor in forming neurofibrillary tangles.
 However, no significant difference between structure of HS obtained from
control and Alzheimer's disease brains.
 Note: Topological separation of tau (in cytosol) from GAGs (extracellular) thus, association can only occur after cell death.
 Heparan sulfate proteoglycans may also play an important role in regulating
amyloid plaque deposition.
Pulmonary Medicine
Role of Selectins in Bronchial Asthma.
 Asthma - hyper-responsiveness of tracheobronchial tree, giving widespread
airway narrowing - changes in severity, either spontaneously or from therapy.
Two dominant pathological features are airway wall inflammation and luminal
obstruction of airways by inflammatory exudate.
 Likely due to antigen-specific IgE antibodies, which become fixed to mast cells
and basophils. Antigen cross-links IgE molecules, triggering an explosive
release of vasoactive, bronchoactive, and chemotactic agents from mast cell
granules into the extracellular milieu.
 Eosinophils may contribute to pathogenesis of asthma in several ways
 Evidence indicates that E and P-selectins are involved in the recruitment of
eosinophils and basophils into the lung.
 Inhibitors of selectin should be explored.
Pulmonary Medicine
Role of Selectins in the Acute Respiratory Distress Syndrome.
 Life-threatening final common pathway of lung injury arising from many
events (e.g., shock, trauma and sepsis).
 Diffuse pulmonary endothelial injury, progressing to pulmonary edema due
increase in capillary permeability.
 Selectins and integrins help circulating neutrophils to adhere to endothelium
and release injurious oxidants, proteolytic enzymes, and arachidonic acid
metabolites, resulting in endothelial cell dysfunction and destruction.
 Many neutrophils and products in bronchoalveolar lavage liquid emphasizing
critical role of inflammatory response.
 Unfulfilled hope - selectin inhibitors used in early stages syndrome, before
progression to lung damage and respiratory failure.
Pulmonary Medicine
Altered Glycosylation of Epithelial Glycoproteins in Cystic Fibrosis (CF)
 CF- common genetic disorder caused by a mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR). Causes defective chloride
conduction across the apical membrane of epithelial cells.
 Associated with increased production of viscous mucins in the gut and lungs,
which cause many of the symptoms.
 Reductions in sialylation and increases in the sulfation and fucosylation of
mucus glycoproteins in CF.
 Higher Golgi pH in CF MAY cause abnormal glycosylation (controversial)
 Major cause of morbidity is colonization of respiratory epithelium by an
alginate-producing form of Pseudomonas.
 Certain glycolipids are Pseudomonas receptors that help to maintain the
colonization. Defects in Golgi sialylation as well as production of a sialidase by
bacteria may help to enhance production of binding targets for colonization.
CHONDROITIN
SULFATE
HYALURONAN
P
GLYCOSAMINOGLYCANS
S
S
Ser-O-
HEPARAN SULFATE
Paroxysmal Nocturnal
Hemoglobinuria:
Somatic Loss of Glycophospholipid Anchors
in Hematopoietic
Stem Cells
N-LINKED CHAINS
S
S
S
S
S
NS
NS
Ac
O-LINKED
CHAIN
GLYCOPHOSPHOLIPID
ANCHOR
P
S
O
Ser/Thr
GLYCOSPHINGOLIPID
-O-Ser
N
Asn
N
Asn
NH 2
INOSITOL
Glycoprotein
Ac
OUTSIDE
Sialic Acids
INSIDE
O-LINKED GlcNAc
O
Ser
Etn
P
P
S
• The first step in biosynthesis of the GPI
anchor requires at least four genes
• One of them, PIG-A is an X-linked gene
Mutation in PNH
Biosynthesis
of GPI anchors
Paroxysmal Nocturnal Hemoglobinuria
 Acquired clonal hematopoietic stem cell disorder - intravascular hemolytic
anemia. Abnormal blood cells lack GPI-anchored proteins due to mutation in
the PIG-A gene.
 Lack of GPI-anchored complement regulatory proteins, such as decayaccelerating factor (DAF) and CD59, results in complement-mediated hemolysis
and hemoglobinuria.
 Factors that determine why mutant clones expand have not been determined.
 Do existing PNH clones have a conditional growth advantage depending on
some factor present in the marrow environment of PNH patients?
 However, cells with PNH phenotype found at frequency of 22 per million in
normal adults. These rare cells collected by flow sorting had PIG-A mutations.
 Thus, PIG-A gene mutations are not sufficient for the development of clinically
evident PNH.
Biosynthesis of O-linked
Glycans
CHONDROITIN
HYALURONAN
SULFATE
P
GLYCOSAMINOGLYCANS
HEPARAN SULFATE
O-Glycans as Antigens in the
Polyagglutinin Syndromes
S
S
S
S
S
Ser-O-
S
S
NS
NS
-O-Ser
Proteoglycan
N-LINKED CHAINS
Ac
O-LINKED
CHAIN
GLYCOPHOSPHOLIPID
ANCHOR
P
S
O
Ser/Thr
N
Asn
N
Asn
NH 2
INOSITOL
Glycoprotein
GLYCOSPHINGOLIPID
OUTSIDE
Sialic Acids
INSIDE
O-LINKED GlcNAc
O
Ser
Etn
P
P
S
Polyagglutination Syndromes
 “Mixed Field Polyagglutination” - acquired condition - red cells become
agglutinable with great majority of adult sera.
 Causes increased turnover of red cells and platelets
 In many instances, red cell membrane has exposed one (or more) latent Oglycan based antigens, i.e. T, Tn or sialylTn.
 Adult sera contain IgM antibodies directed against these antigens. When
targets are exposed, cells are polyagglutinable upon testing with these sera.
 Transient Mixed Field Polyagglutination can be seen after various bacterial
infections, probably due to entry of bacterial enzymes into the bloodstream
 In chronic cases, Core 1 Gal-T activity that synthesizes T antigen is low in
some affected cells. Gene appears to be repressed instead of mutated. Is the
primary defect in Cosmc on the X chromosome?
 The chronic form can be precursor of acute leukemia
CHONDROITIN
SULFATE
HYALURONAN
Polylactosamines as
GLYCOSAMINOAntigens in
Cold
GLYCANS
Agglutinin Syndromes
Ser-OI Antigen
HEPARAN SULFATE
S
S
S
NS
P
S
S
S
NS
-O-Ser
Proteoglycan
i Antigen
N-LINKED CHAINS
O-LINKED P
CHAIN
GLYCOPHOSPHOLIPID
ANCHOR
S
N
O
Asn
Ser/Thr
N-LINKED
CHAIN
N
Asn
NH 2
INOSITOL
Glycoprotein
GLYCOSPHINGOLIPID
OUTSIDE
Sialic Acids
INSIDE
O-LINKED GlcNAc
O
Ser
Etn
P
P
S
Cold Agglutinin Syndromes
 Acquired Hemolytic Anemias caused by cold-reactive IgM antibodies that
agglutinate normal RBCs in the cold, and fix complement, resulting in lysis in
warmer regions.
 Many of these antibodies react with the i / I antigens and are actually encoded
by germline sequences.
 Mycoplasma pneumoniae infections associated with cold agglutinins that may
cause a mild to moderate auto-immune hemolytic anemia.
 Major host cell receptor for Mycoplasma is sialylated i/I
 Hypothesis:
Mycoplasma
I Antigen
Mycoplasma
Antibody 1
Anti-Id
Antibody 2
I Antigen
HEMPAS (hereditary erythroblastic multinuclearity
with positive acidified serum lysis test)
 Congenital dyserythropoietic anemia type II or HEMPAS is an inherited
anemia caused by a glycosylation deficiency.
 Red cell membrane glycoproteins (e.g.,band 3 & 4.5, which are normally
glycosylated with polylactosamines lack these glycans, which
accumulate on red glycolipids instead.
 HEMPAS red cells carry incompletely processed N-glycans, suggesting
defects in the N-acetylglucosaminyltransferase II (GnT-II) or alphamannosidase II (M-II) steps
 Family studies identified two cases in which the M-II gene is defective.
HYALURONAN
Altered expression of
N-Glycans and CHONDROITIN
SULFATE
GLYCOSAMINOPolylactosamines
in HEMPAS
HEPARAN
SULFATE
GLYCANS
(Hereditary Erythroblastic Multinuclearity
with Positive Acidified Serum lysis test)
P
S
S
Ser-O-
S
S
NS
-O-Ser
Proteoglycan
N-LINKED CHAINS
O-LINKED P
CHAIN
GLYCOPHOSPHOLIPID
ANCHOR
S
N-LINKED CHAIN
(INCOMPLETELY
PROCESSED)
Glycoprotein
N
O
Asn
Ser/Thr
GLYCOSPHINGOLIPID
(LARGER )
N
Asn
OUTSIDE
INSIDE
O-LINKED GlcNAc
O
Ser
Etn
P
NH 2
INOSITOL
P
S
HEMPAS (hereditary erythroblastic multinuclearity
with positive acidified serum lysis test)
 Mutant mice in which the MII gene was inactivated by homologous
recombination resulted in a HEMPAS-like phenotype.
 Linkage analysis of another kindred excluded M-II and GnT-II as
primary defects
 Regardless of which gene is defective, HEMPAS is characterized by
incomplete processing of N-glycans.
 Further studies of HEMPAS may identify hitherto unknown factors
affecting N-glycan synthesis
 Some patients who present late in life may have an acquired form of the
disease?
Acquired Glycosylation
Changes in Relation to Human Disease
 CARDIOVASCULAR MEDICINE
 DERMATOLOGY
 ENDOCRINOLOGY AND METABOLISM
 GASTROENTEROLOGY
 HEMATOLOGY
 IMMUNOLOGY AND RHEUMATOLOGY
 INFECTIOUS DISEASE
 NEUROLOGY AND PSYCHIATRY
 PULMONARY MEDICINE
 ONCOLOGY (already covered in lecture 35)