Old gene, new phenotype: Mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses

Journal of Medical Genetics

Volumn 52, Issue 10, 2015, Pages 666-675

  Farhan, Sali M K ^a,b   Wang, Jian ^a   Robinson, John F ^a   Prasad, Asuri N ^c,d   Anthony Rupar, C ^b,c,d   Siu, Victoria M ^b,c,d   Hegele, Robert A ^a,b  

^a ROBARTS RESEARCH INSTITUTE   (Canada)

^b WESTERN UNIVERSITY   (Canada)

^c LONDON HEALTH SCIENCES CENTRE   (Canada)

^d CHILDREN S HEALTH RESEARCH INSTITUTE   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

EXOSTOSIN 2; HEPARAN SULFATE; PROTEIN DERIVATIVE; UNCLASSIFIED DRUG; EXOSTOSIN-2; N ACETYLGLUCOSAMINYLTRANSFERASE;

ARTICLE; CASE REPORT; CHILD; CLINICAL FEATURE; CONTROLLED STUDY; DEVELOPMENTAL DISORDER; ENZYME SYNTHESIS; GENE MUTATION; GENE SEQUENCE; GENOTYPE; HOMOZYGOSITY; HUMAN; HUMAN CELL; MACROCEPHALY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; SCOLIOSIS; SEIZURE; SEQUENCE ANALYSIS; ADULT; DEFICIENCY; DEVELOPMENTAL DISABILITIES; DNA SEQUENCE; EXOSTOSIS; FEMALE; GENETICS; MALE; METABOLISM; MUTATION; PEDIGREE; PRESCHOOL CHILD; SEIZURES;

ADULT; CHILD, PRESCHOOL; DEVELOPMENTAL DISABILITIES; EXOSTOSES; FEMALE; HEPARITIN SULFATE; HUMANS; MALE; MUTATION; N-ACETYLGLUCOSAMINYLTRANSFERASES; PEDIGREE; SEIZURES; SEQUENCE ANALYSIS, DNA;

EID: 84945450405     PISSN: 00222593     EISSN: 14686244     Source Type: Journal    
DOI: 10.1136/jmedgenet-2015-103279     Document Type: Article

References (40)

1. Kreuger J, Spillmann D, Li JP, Lindahl U. Interactions between heparan sulfate and proteins: the concept of specificity. J Cell Biol 2006;174:323-7.
2. Perrimon N, Bernfield M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 2000;404:725-8.
3. Venero Galanternik M, Kramer KL, Piotrowski T. Heparan sulfate proteoglycans regulate Fgf signaling and cell polarity during collective cell migration. Cell Rep 2015;S2211-1247(14)01096-1.
4. Astudillo P, Larrain J. Wnt signaling and cell-matrix adhesion. Curr Mol Med 2014;14:209-20.
5. Shimokawa K, Kimura-Yoshida C, Nagai N, Mukai K, Matsubara K, Watanabe H, Matsuda Y, Mochida K, Matsuo I. Cell surface heparan sulfate chains regulate local reception of FGF signaling in the mouse embryo. Dev Cell 2011;21:257-72.
6. Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 2007;446:1030-7.
7. Bandtlow CE, Zimmermann DR. Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 2000;80:1267-90.
8. Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet 1996;14:25-32.
9. McCormick C, Duncan G, Goutsos KT, Tufaro F. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 2000;97:668-73.
10. Ahn J, Ludecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet 1995;11:137-43.
11. Korn JM, Kuruvilla FG, McCarroll SA, Wysoker A, Nemesh J, Cawley S, Hubbell E, Veitch J, Collins PJ, Darvishi K, Lee C, Nizzari MM, Gabriel SB, Purcell S, Daly MJ, Altshuler D. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 2008;40:1253-60.
12. Rabbee N, Speed TP. A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics 2006;22:7-12.
13. Lander ES, Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 1987;236:1567-70.
14. Broman KW, Weber JL. Long homozygous chromosomal segments in reference families from the centre d'Etude du polymorphisme humain. Am J Hum Genet 1999;65:1493-500.
15. Presto J, Thuveson M, Carlsson P, Busse M, Wilen M, Eriksson I, Kusche-Gullberg M, Kjellen L. Heparan sulfate biosynthesis enzymes EXT1 and EXT2 affect NDST1 expression and heparan sulfate sulfation. Proc Natl Acad Sci USA 2008;105: 4751-6.
16. Nadanaka S, Kitagawa H. Heparan sulphate biosynthesis and disease. J Biochem 2008;144:7-14.
17. Shevelev OB, Rykova VI, Fedoseeva LA, Leberfarb EY, Dymshits GM, Kolosova NG. Expression of Ext1, Ext2, and heparanase genes in brain of senescence-accelerated OXYS rats in early ontogenesis and during development of neurodegenerative changes. Biochemistry (Mosc) 2012;77:56-61.
18. Maeda N, Ishii M, Nishimura K, Kamimura K. Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem Res 2011;36: 1228-40.
19. Stickens D, Brown D, Evans GA. EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Dev Dyn 2000;218:452-64.
20. Ropero S, Setien F, Espada J, Fraga MF, Herranz M, Asp J, Benassi MS, Franchi A, Patino A, Ward LS, Bovee J, Cigudosa JC, Wim W, Esteller M. Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells. Hum Mol Genet 2004;13: 2753-65.
21. van Horssen J, Wesseling P, van den Heuvel LP, de Waal RM, Verbeek MM. Heparan sulphate proteoglycans in Alzheimer's disease and amyloid-related disorders. Lancet Neurol 2003;2:482-92.
22. Fischer S, Filipek-Gorniok B, Ledin J. Zebrafish Ext2 is necessary for Fgf and Wnt signaling, but not for Hh signaling. BMC Dev Biol 2011;11:53.
23. Norton WH, Ledin J, Grandel H, Neumann CJ. HSPG synthesis by zebrafish Ext2 and Extl3 is required for Fgf10 signalling during limb development. Development 2005;132:4963-73.
24. Nurcombe V, Ford MD, Wildschut JA, Bartlett PF. Developmental regulation of neural response to FGF-1 and FGF-2 by heparan sulfate proteoglycan. Science 1993;260:103-6.
25. Reuter MS, Musante L, Hu H, Diederich S, Sticht H, Ekici AB, Uebe S, Wienker TF, Bartsch O, Zechner U, Oppitz C, Keleman K, Jamra RA, Najmabadi H, Schweiger S, Reis A, Kahrizi K. NDST1 missense mutations in autosomal recessive intellectual disability. Am J Med Genet A 2014;164A:2753-63.
26. Ryckx A, Somers JF, Allaert L. Hereditary multiple exostosis. Acta Orthop Belg 2013;79:597-607.
27. Busse-Wicher M, Wicher KB, Kusche-Gullberg M. The exostosin family: proteins with many functions. Matrix Biol 2014;35:25-33.
28. Huegel J, Sgariglia F, Enomoto-Iwamoto M, Koyama E, Dormans JP, Pacifici M. Heparan sulfate in skeletal development, growth, and pathology: the case of hereditary multiple exostoses. Dev Dyn 2013;242:1021-32.
29. Stancheva-Ivanova MK, Wuyts W, van Hul E, Radeva BI, Vazharova RV, Sokolov TP, Vladimirov BY, Apostolova MD, Kremensky IM. Clinical and molecular studies of EXT1/EXT2 in Bulgaria. J Inherit Metab Dis 2011;34:917-21.
30. Palka C, Alfonsi M, Mohn A, Guanciali Franchi P, Chiarelli F, Calabrese G. Delayed diagnosis of potocki-shaffer syndrome in a woman with multiple exostoses and mental retardation. Mol Syndromol 2012;2:259-61.
31. Kim HG, Kim HT, Leach NT, Lan F, Ullmann R, Silahtaroglu A, Kurth I, Nowka A, Seong IS, Shen Y, Talkowski ME, Ruderfer D, Lee JH, Glotzbach C, Ha K, Kjaergaard S, Levin AV, Romeike BF, Kleefstra T, Bartsch O, Elsea SH, Jabs EW, MacDonald ME, Harris DJ, Quade BJ, Ropers HH, Shaffer LG, Kutsche K, Layman LC, Tommerup N, Kalscheuer VM, Shi Y, Morton CC, Kim CH, Gusella JF. Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. Am J Hum Genet 2012;91:56-72.
32. Kozlowski K, Harrington G, Barylak A, Bartoszewica B. Multiple exostoses-mental retardation syndrome (Ale-Calo or M.E.M.R. syndrome). Clin Pediatr (Phila) 1977;16:219-24.
33. Ludecke HJ, Wagner MJ, Nardmann J, La Pillo B, Parrish JE, Willems PJ, Haan EA, Frydman M, Hamers GJ, Wells DE, et al. Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Hum Mol Genet 1995;4:31-6.
34. Stickens D, Zak BM, Rougier N, Esko JD, Werb Z. Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development 2005;132:5055-68.
35. Lin X, Wei G, Shi Z, Dryer L, Esko JD, Wells DE, Matzuk MM. Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Dev Biol 2000;224:299-311.
36. Koziel L, Kunath M, Kelly OG, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 2004;6:801-13.
37. Yamada S, Busse M, Ueno M, Kelly OG, Skarnes WC, Sugahara K, Kusche-Gullberg M. Embryonic fibroblasts with a gene trap mutation in Ext1 produce short heparan sulfate chains. J Biol Chem 2004;279:32134-41.
38. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 1998;273:26265-8.
39. Busse M, Kusche-Gullberg M. In vitro polymerization of heparan sulfate backbone by the EXT proteins. J Biol Chem 2003;278:41333-7.
40. Busse M, Feta A, Presto J, Wilen M, Gronning M, Kjellen L, Kusche-Gullberg M. Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation. J Biol Chem 2007;282:32802-10.