congenital disorders of glycosylation (CDG): an exercise in dysmorphology

Transcription

1 congenital disorders of glycosylation (CDG): an exercise in dysmorphology Jaak Jaeken Centre for Metabolic Disease Katholieke Universiteit Leuven, Belgium

2 outline glycosylation: definition and pathways CDG: nomenclature and classification CDG dysmorphy and dysmorphy syndromes

3 outline glycosylation: definition and pathways CDG: nomenclature and classification CDG dysmorphy and dysmorphy syndromes

4 glycosylation synthesis of glycans and their attachment to other compounds glycoconjugates

5 importance of glycosylation glycans play important and very diverse roles in the functions and metabolism of glycoconjugates about 1% of genes participate in glycosylation at least 50% of human proteins are glycoproteins

6 glycosylation pathways protein N-glycosylation protein O-glycosylation lipid glycosylation

7 N-glycan sia gal man O-glycan (core 1) N-gal fuc N-glu SER /THR ASN

8 N-glycosylation cytosol ER Golgi assembly attachment processing

9 GLU CYTOSOL FRU 6-P MAN 6-P MAN 1-P LACTATE ENDOPLASMIC RETICULUM GDP-MAN

10 P Fru 6-P P ER GDP-Man P P P P P GDP Golgi cytoplasma

11 Golgi N-glycosylation

12 O-glycosylation only assembly, no processing occurs mostly in Golgi great diversity of O-glycan structures (mucins, GAGs,...)

13 outline glycosylation: definition and pathways CDG: nomenclature and classification CDG: dysmorphy and dysmorphy syndromes

14 new CDG nomenclature gene symbol (not in italics) followed by: - CDG e.g. PMM2-CDG (CDG-Ia)

15 CDG classification defects in protein N-glycosylation (n=15) defects in protein O-glycosylation (n=9) defects in lipid glycosylation (n=2) defects in multiple glycosylation pathways other pathways (n=16)

16 outline glycosylation: definition and pathways CDG: nomenclature and classification CDG dysmorphy and dysmorphy syndromes

17 dysmorphy in N-glycosylation defects PMM2 CDG MGAT2 - CDG

18 PMM2 CDG (CDG-Ia) phosphomannomutase 2 deficiency

19 GLU PMM2 FRU 6-P MAN 6-P MAN 1-P LACTATE ENDOPLASMIC RETICULUM GDP-MAN

20

21 MGAT2 CDG (CDG-IIa) N-acetylglucosaminyltransferase 2 deficiency

22 Golgi N-glycosylation

23 MGAT2 - CDG GOLGI

24

25

26 Mgat2-null mouse Wang et al 2001

27 dysmorphology in O-glycosylation defects O-xylosylglycan synthesis defects O-GalNAcglycan synthesis defects O-mannosylglycan synthesis defects O-fucosylglycan synthesis defects

28 O-xylosylgycan synthesis defects B4GALT7-CDG: progeroid syndrome EXT1/EXT2 CDG: hereditary multiple exostoses

29 B4GALT7 CDG galactosyltransferase I deficiency protein O xyl gal gal glua N-glu n

30 B4GALT7 - CDG Faiyaz-Ul-Haque et al 2004 Knesse et al 1987

31 EXT1/EXT2 - CDG hereditary multiple exostoses protein O xyl gal gal glua N-glu n

32 EXT1/EXT2 - CDG

33 GALNT3 - CDG O-N-acetylgalactosaminylglycan synthesis defect (familial tumoral calcinosis, hyperphosphatemic form)

34 familial tumoral calcinosis GALNT3 - CDG GLYCAN GalNAcT3 SER /THR

35 Topaz et al 2004

36 Pathogenesis of HFTC GalNacT3 O-glycosylation FGF23 degradation - + renal P reabsorption hyperphosphatemia induction of FGF7 (dermis) triggers matrix metalloproteinases mediate ectopic calcification

37 SLC35D1 - CDG O-xylose/N-acetylgalactosaminyl glycan synthesis defect (Schneckenbecken dysplasia)

38 SLC35D1 - CDG Furuichi et al 2009

39 O-mannosylglycan synthesis defects POMT1/POMT2-CDG: Walker-Warburg syndrome POMGNT1-CDG: muscle-eye-brain disease

40 Walker-Warburg syndrome POMT1/POMT2 - CDG ASN - dystroglycan glycan WWS THR/SER

41 muscle-eye-brain disease POMGNT1 - CDG ASN - dystroglycan glycan MEBD THR/SER

42 muscle-eye-brain disease POMGNT1 - CDG Clement et al 2008

43 O-fucosylglycan synthesis defects LFNG-CDG: spondylocostal dysostosis type 3 B3GALTL-CDG: Peters plus syndrome

44 LFNG-CDG spondylocostal dysostosis type 3 (SCD3; notch pathway) SER THR fucose N-acetylglucosamine

45 SCD3: severe vertebral phenotype Sparrow et al 2006

46 B3GALTL-CDG Peters plus syndrome SER THR fucose glucose

47 Peters plus syndrome B3GALTL-CDG Maillette de Buy Wenniger Prick and Hennekam 2002

48 dysmorphy in defects of multiple glycosylation pathways COG1-CDG: cerebrocostomandibular syndrome (AR) ATP6VOA2-CDG: cutis laxa type 2, wrinkly skin syndrome, de Barsy syndrome

49 COG complex: shuttle ER Golgi

50 COG complex lobe A lobe B

51 COG1-CDG cerebrocostomandibular syndrome Zeevaert et al 2009

52 ATP6V0A2-CDG cutis laxa type 2 wrinkly skin syndrome de Barsy syndrome Hucthagowder et al 2009

53 non-syndromic dysmorphic features in CDG (external) dwarfism microcephaly skeletal abnormalities facial dysmorphy coarse face micrognathia iris coloboma wrinkled skin ichthyosis

54 non-syndromic dysmorphic features in CDG (internal) cerebellar hypoplasia Dandy-Walker malformation neuronal heterotopia retinal coloboma cardiac septal defects hepatomegaly urological/genital abnormalities

55 CDG CDG CDG CDG CDG CDG CDG CDG CDG CDG CDG CDG CDG CDG Pandora s box CDG

56 look for CDG in any unexplained dysmorphy syndrome!

57 collaborating teams LEUVEN L. Keldermans V. Race W. Vleugels G. Matthijs E. Reynders W. Annaert LILLE F. Foulquier I. Bongaers S. Van Aerschot B. Van den Heuvel R. Zeevaert J. Jaeken EUROGLYCANET