CCRC Course on Glycobiology Glycosylation disorders – April 14 2009 Presentation ................................................................................... page 2 Summary table ............................................................................... page 46 Proposal for new nomenclature ..................................................... page 49 Mutations in lipid-linked oligosaccharide biosynthesis................... page 51 Thierry Hennet, PhD University of Zürich Institute of Physiology Winterthurerstrasse 190 CH-8057 Zürich [email protected]
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Glycosylation disorders – April 14 2009 › ~glycobiology › CCRC course (Hennet).pdf · Diseases of O-fucosylation Mutations in DLL3 (ligand of Notch) also causes spondylocostal
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POMT1POMGnT1FukutinFukutin-related protein (FRP)Large
POMT1/POMT2
POMGnT1
Fukutin
LARGE
FKRP
Walker Warburg
Muscle eye brain
FCMD
MDC1D
MDC1C
Limb girdle MD
CMD +MR
Extent of residual α-DG glycosylation likely to be important
Severity
For recent genotype/phenotype correlation studySee Godfrey et al. Brain 130:2725-2735 (2007)
Gene/phenotype relationships
N-glycans O-glycans C-glycans
GAG GPIanchor
Glycolipids Cytoplasmic/nuclearglycans
N S/T S/T S/T W
Cer CerPI S/TS
S/T Hyl
Glycoconjugate classes in vertebrates
αβ
β
α β α β α
ββ βα
α
α
α
ββ
β
β
β
β
α α
P P
FGF2 FGF2
FGF2
HGF
ProteoglycanFGF2-Receptor
Diseases of glycosylation: exostoses
EXT1 (chr 8q24)EXT2 (chr 11p12)EXT3 (chr 19p)
B4GALT7 (chr 5q32)
00FGF18
FGF2
BMPs
Normal Exostoses
Endochondral ossification
N-glycans O-glycans C-glycans
GAG GPIanchor
Glycolipids Cytoplasmic/nuclearglycans
N S/T S/T S/T W
Cer CerPI S/TS
S/T Hyl
Glycoconjugate classes in vertebrates
αβ
β
α β α β α
ββ βα
α
α
α
ββ
β
β
β
β
α α
Enzymes of O-fucosylation/glucosylation
S/T
6 β4GalT
3 β3GlcNAcT
3 ST3GalT
1 β3GlcT 2 OFUT
lunatic fringeradical fringemanic fringe
S/T
XylT genes notcloned yet
1 OGLCT
Peters Plus syndrome
Figure 2 from Oberstein et al.
Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.Oberstein et al. (2006) Am J Hum Genet, 79:562-566
Birth weight below 3rd percentile, psychomotor retardation, hypertelorism, short limbs, short hands, eye anterior chamber defect
Diseases of O-fucosylation
Mutations in DLL3 (ligand of Notch) also causes spondylocostal dysostosis in humans (OMIM 602768)
Hes7
Lunatic fringe disruption causes spondylocostal dysostosis in the mouse and in humans (OMIM 609813).See: Evrard Y.A. et al. (1998) Nature 394, 377 – 381
N-glycans O-glycans C-glycans
GAG GPIanchor
Glycolipids Cytoplasmic/nuclearglycans
N S/T S/T S/T W
Cer CerPI S/TS
S/T Hyl
Glycoconjugate classes in vertebrates
αβ
β
α β α β α
ββ βα
α
α
α
ββ
β
β
β
β
α α
failure to thrivepsychomotor retardationhypotoniacerebellum hypoplasiaataxiahormonal disordersepilepsystrabismuscoagulation disorderstissue fibrosis
∆GnT5: T-cell hyperreactivity,endocytosis of membranereceptors
M1V
N
C
frameshift(stop AA34)
C9YF11C
G15R, G15EG15A
T18S
P20S
Ex skip
L32R
L35X
Q37H
V44AV44F
K51R
frameshift(stop AA58)
Ex skip
Y64CD65Y
V67MV67G
P69S
Y76CEx skip
E93A
N101K
C103FL104V
Y106C
A108Vframeshift(stop AA126)
P113L
G117R
F119LI120T
R123XR123Q
V129M
frameshift(stop AA152)
P131A
I132TI132NI132F
frameshift(stop AA152)
E139K
R141H / R141C
F144L D148N
frameshift(stop AA151)
I153T
E151G F157S
R162W
F172VG176V
G175RQ177H
F183SD185G D188G
frameshift (stop AA199)
C192G
R194XH195R
E197A
F206T, F206LF207SG208A
G214SEx skip
del ex8ins 41AA
N216I / N216SD217E
H218L
D223ED223N
T226S
G228 CG228R
Y229S
V231M A233T
R238G / R238P
T237RT237M
R239WC241S
L243P
R21GQ22X
G42R
G57R
PMM2
A selection pressure for glycosylation defects?
Carrier frequency of 1 in 70!
Diagnose
A
B
AB
O
Anti-BSerum
Anti-ASerum
Anti-AAnti-BSerum
GalFuc
GlcNAc
Gal
GalFuc
GlcNAc
GalFuc
GlcNAc
GalNAc
O A B
The ABO-System:
Glycan polymorphisms: ABO blood groups
Loss of α1-3 GalT in Old-World primates
GlcNAc
Gal
R
GlcNAc
Gal
R
Gal
α1-3 GalT
Loss of CMP-Neu5Ac hydroxylase in humans
Norovirus
CBC News – Canada Friday, January 19, 2007
Saskatoon's Royal University Hospital, the city's biggest, was closed to visitors Friday after an outbreak of Norwalk virus. More than 40 patients and staff have fallen ill with the norovirus infection. Managers are trying to contain the outbreak.The virus is easily spread on surfaces and through the air. Symptoms include severe stomach cramps, vomiting and diarrhea. The illness is rarely fatal, but it can be a serious health concern for seniors and babies.
"Well, in our country," said Alice, still panting a little, "you'd generally get to somewhere else — if you run very fast for a long time, as we've been doing.„
"A slow sort of country!" said the Queen. "Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"
CDG-IIc SLC35C1 import of GDP-Fuc into Golgi and export of
GMP
266265
CDG-IId B4GALT1 β1-4 galactosyltransferase 607091
CDG-IIf SLC35A1 import of CMP-Sia into Golgi 603585
Hereditary inclusion
body myopathy
GNE UDP-N-acetylglucosamine 2-epimerase 600737
CDG-Im DK1 dolichol kinase 610768
“CDG-Is” pending dolichol reductrase unpublished
Trafficking disorders
CDG-IIe COG7 vesicular trafficking 608779
CDG-IIg COG1 vesicular trafficking 611209
CDG-IIh COG8 vesicular trafficking 611182
CDG-IIi COG4 vesicular trafficking unpublished
CDG-IIj COG5 vesicular trafficking unpublished
Autosomal recessive
cutis laxa
ATPV0A2 H+/ATPase, pH regulation in Golgi 219200
CDG nomenclature: time for a change! Jaak Jaeken1,2, Thierry Hennet3 , Gert Matthijs4, Hudson Freeze5
2Center for Metabolic Disease, Katholieke Universiteit Leuven, BE-3000 Leuven, Belgium 3Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland 4Center for Human Genetics, Katholieke Universiteit Leuven, BE-3000 Leuven, Belgium 5Sanford Children’s Health Research Center, Burnham Institute of Research, La Jolla, CA 92037, USA 1To whom correspondence should be addressed: Tel: +32 16 343820; Fax: +32 16 343842; e-mail: jaak [email protected] Congenital disorders of glycosylation (CDG) are a rapidly growing disease family with nearly 40 diseases reported since its first clinical description in 1980 (1). The large majority of these are diseases of protein hypoglycosylation, but in recent years several defects in lipid glycosylation have also been identified (2,3). Most protein glycosylation disorders are due to defects in the N-glycosylation pathway, the remaining ones affecting the O-glycosylation disorders or combined N- and O-glycosylation pathways. No defects in C-glycosylation have been detected yet. The first described CDG patients were shown to have an abnormal serum transferrin (Tf) isoelectrofocusing (IEF) pattern with increases in the di- and asialotransferrin fractions (4 ). They were found to have deficient phosphomannomutase (PMM) activity (5) and mutations in the PMM2 gene (6). PMM deficient patients were designated as CDG-Ia. Subsequently, a patient was discovered with a serum Tf IEF pattern characterized by increases not only of the even (2 and 0) but also of the uneven (3 and 1) sialoTf bands (7). Since these patterns were qualitatively different, we called the latter a type 2 pattern as opposed to the type 1 pattern seen in PMM deficiency. In the patient with the type 2 pattern, a deficiency was demonstrated to be in a Golgi glycosyltransferase, namely N-acetylglucosaminyltransferase II (8). This disease was labelled CDG-IIa. New patients were classified as CDG-I or CDG-II according to the Tf IEF pattern, and each new defect took the next letter of the alphabet.
We presently count 14 CDG-I diseases (CDG-Ia up to CDG-In), and 8 CDG-II diseases (CDG-IIa up to CDG-IIh). Since this nomenclature is based on the Tf IEF pattern, it relates only to N-glycosylation diseases associated with deficient sialylation. Gradually it became clear that CDG-I defects were limited to defects in pre-ER or ER proteins whereas CDG-II defects were caused by defects in Golgi or Golgi-associated proteins. However, some of these disorders also show abnormal O-glycosylation such as the COG defects (review in 9) and the V-ATPase defect in cutis laxa type II (10). Also, it appeared that a patient with an alpha-glucosidase-II deficiency in the ER had a normal Tf IEF pattern (11). Still this patient was labeled as CDG-IIb, which is an inconsistency of this classification. For this reason and for a number of other reasons explained elsewhere (12 ), we strongly suggest that this
nomenclature should be discontinued in favour of a transparent designation of glycosylation disorders and that it be applied to new and established types of CDG. We propose using only the official gene name, with the option of adding CDG in parentheses after the gene name (list of approved gene names at http://www.genenames.org). A classification of the known types of CDG, along with the traditional and new nomenclature, is shown in the Table (12).
References
1. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG deficiency, increased serum arylsulfatase A and increased CSF protein: a new syndrome? Pediatr Res 1980; 14: 179
2. Freeze HH. Genetic defects in the human glycome. Nat Rev Genet 2006; 7: 537-551 3. Jaeken J, Matthijs G. Congenital disorders of glycosylation: a rapidly expanding
disease family. Annu Rev Genomics Hum Genet 2007; 8: 261-278 4. Jaeken J, van Eijk HG, van der Heul C, Corbeel L, Eeckels R, Eggermont E. Sialic
acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta 1984; 144: 245-247
5. Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995; 377: 318-320
6. Matthijs G, Schollen E, Pardon E, et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 1997; 16: 88-92. Erratum in Nat Genet 1997; 16: 316
7. Ramaekers VT, Stibler H, Kint J, Jaeken J. A new variant of the carbohydrate deficiënt glycoproteins syndrome. J Inherit Metab Dis 1991; 14: 385-388
8. Jaeken J, Schachter H, Carchon H, De Cock P, Coddeville B, Spik G. Carbohydrate deficiënt glycoprotein syndrome type II: a deficiency in Golgi localised N-acetylglucosaminyltransferase II. Arch Dis Child 1994; 71: 123-127
9. Zeevaert R, Foulquier F, Jaeken J, Matthijs G. Deficiencies in subunits of the Conserved Oligomeric Golgi complex define a novel group of Congenital Disorders of Glycosylation. Mol Genet Metab 2008; 93: 15-21
10. Kornak U, Reynders E, Dimopoulou A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 2008; 40: 32-34
11. De Praeter CM, Gerwig GJ, Bause E, et al. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet 2000; 66: 1744-1756
12. Jaeken J, Hennet T, Freeze H, Matthijs G. About nomenclature of Congenital Disorders of Glycosylation (CDG). J Inherit Metab Dis 2008 Oct 24 (Epub ahead of print)