Abnormal Proteoglycan Synthesis Due to Gene Defects Causes Skeletal Diseases with Overlapping Phenotypes

Abstract

In recent years, massively parallel sequencing technologies have helped us to identify novel disease genes and solve the mysteries behind rare diseases. Today, we know that some diseases with many overlapping and distinct clinical features, as presented in this review, can be caused by mutations in genes that encode enzymes playing crucial roles at different steps of the exact same pathway. In this review, we exclusively focused on 5 genes – XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3 – that encode enzymes involved in the biosynthesis of the common tetrasaccharide linker region of proteoglycans and review the associated diseases, also referred to as linkeropathies, by summarizing the cases reported in literature. Since proteoglycans are essential macromolecules in development, signaling and homeostasis of many tissues and organs, mutations in these genes can affect many organs; including bone, cartilage, eyes, ears, heart, and skin. Short stature, developmental delay, facial dysmorphism, and skeletal dysplasias are some of the common features observed in patients with mutations in these genes. Among these genes, XYLT2 mutations cause a relatively distinct phenotype, the so-called spondyloocular syndrome, which is characterized by clinical presentation of a very severe childhood-onset primary osteoporosis, cataract, and hearing impairment. The full phenotype spectrum of diseases mentioned here is likely to expand with additional clinical reports and further molecular studies.

Key words

skeletal dysplasia - glycosaminoglycan - spondyloocular syndrome - osteoporosis - Ehlers-Danlos syndrome

• References

• 1 Makitie O. Causes, mechanisms and management of paediatric osteoporosis. Nat Rev Rheumatol 2013; 9: 465-475
• 2 Hori M, Shimizu Y, Fukumoto S. Minireview: fibroblast growth factor 23 in phosphate homeostasis and bone metabolism. Endocrinology 2011; 152: 4-10
• 3 Rivadeneira F, Makitie O. Osteoporosis and Bone Mass Disorders: From Gene Pathways to Treatments. Trends Endocrinol Metab 2016; 27: 262-281
• 4 Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D, Spranger J, Superti-Furga A, Warman M, Unger S. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 2015; 167A: 2869-2892
• 5 Vertel BM, Walters LM, Flay N, Kearns AE, Schwartz NB. Xylosylation is an endoplasmic reticulum to Golgi event. J Biol Chem 1993; 268: 11105-11112
• 6 Stoolmiller AC, Horwitz AL, Dorfman A. Biosynthesis of the chondroitin sulfate proteoglycan. Purification and properties of xylosyltransferase. J Biol Chem 1972; 247: 3525-3532
• 7 Knudson CB, Knudson W. Cartilage proteoglycans. Semin Cell Dev Biol 2001; 12: 69-78
• 8 Sanderson RD. Heparan sulfate proteoglycans in invasion and metastasis. Semin Cell Dev Biol 2001; 12: 89-98
• 9 Perrimon N, Bernfield M. Cellular functions of proteoglycans–an overview. Semin Cell Dev Biol 2001; 12: 65-67
• 10 Yamaguchi Y. Heparan sulfate proteoglycans in the nervous system: their diverse roles in neurogenesis, axon guidance, and synaptogenesis. Semin Cell Dev Biol 2001; 12: 99-106
• 11 Miyake N, Kosho T, Matsumoto N. Ehlers-Danlos syndrome associated with glycosaminoglycan abnormalities. Adv Exp Med Biol 2014; 802: 145-159
• 12 Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 2007; 446: 1030-1037
• 13 Bulow HE, Hobert O. The molecular diversity of glycosaminoglycans shapes animal development. Annu Rev Cell Dev Biol 2006; 22: 375-407
• 14 Sugahara K, Mikami T, Uyama T, Mizuguchi S, Nomura K, Kitagawa H. Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr Opin Struct Biol 2003; 13: 612-620
• 15 Wilson IB. The never-ending story of peptide O-xylosyltransferase. Cell Mol Life Sci 2004; 61: 794-809
• 16 Wopereis S, Lefeber DJ, Morava E, Wevers RA. Mechanisms in protein O-glycan biosynthesis and clinical and molecular aspects of protein O-glycan biosynthesis defects: a review. Clin Chem 2006; 52: 574-600
• 17 Cortes M, Baria AT, Schwartz NB. Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate. Development 2009; 136: 1697-1706
• 18 Koziel L, Kunath M, Kelly OG, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Developmental Cell 2004; 6: 801-813
• 19 Habicher J, Haitina T, Eriksson I, Holmborn K, Dierker T, Ahlberg PE, Ledin J. Chondroitin/dermatan sulfate modification enzymes in zebrafish development. PloS One 2015; 10: e0121957
• 20 Hayes AJ, Mitchell RE, Bashford A, Reynolds S, Caterson B, Hammond CL. Expression of glycosaminoglycan epitopes during zebrafish skeletogenesis. Dev Dyn 2013; 242: 778-789
• 21 Maeda N, Ishii M, Nishimura K, Kamimura K. Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem Res 2011; 36: 1228-1240
• 22 Munns CF, Fahiminiya S, Poudel N, Munteanu MC, Majewski J, Sillence DO, Metcalf JP, Biggin A, Glorieux F, Fassier F, Rauch F, Hinsdale ME. Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects. Am J Hum Genet 2015; 96: 971-978
• 23 Taylan F, Costantini A, Coles N, Pekkinen M, Heon E, Siklar Z, Berberoglu M, Kampe A, Kiykim E, Grigelioniene G, Tuysuz B, Makitie O. Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum. J Bone Miner Res 2016; 31: 1577-1585
• 24 Tomatsu S, Almeciga-Diaz CJ, Montano AM, Yabe H, Tanaka A, Dung VC, Giugliani R, Kubaski F, Mason RW, Yasuda E, Sawamoto K, Mackenzie W, Suzuki Y, Orii KE, Barrera LA, Sly WS, Orii T. Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab 2015; 114: 94-109
• 25 Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford) 2011; 50 (Suppl. 05) v4-12
• 26 Condac E, Silasi-Mansat R, Kosanke S, Schoeb T, Towner R, Lupu F, Cummings RD, Hinsdale ME. Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis. Proc Natl Acad Sci USA 2007; 104: 9416-9421
• 27 Roch C, Kuhn J, Kleesiek K, Gotting C. Differences in gene expression of human xylosyltransferases and determination of acceptor specificities for various proteoglycans. Biochem Biophys Res Commun 2010; 391: 685-691
• 28 Cuellar K, Chuong H, Hubbell SM, Hinsdale ME. Biosynthesis of chondroitin and heparan sulfate in chinese hamster ovary cells depends on xylosyltransferase II. J Biol Chem 2007; 282: 5195-5200
• 29 Mis EK, Liem Jr. KF, Kong Y, Schwartz NB, Domowicz M, Weatherbee SD. Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length. Develop Biol 2014; 385: 67-82
• 30 Schreml J, Durmaz B, Cogulu O, Keupp K, Beleggia F, Pohl E, Milz E, Coker M, Ucar SK, Nurnberg G, Nurnberg P, Kuhn J, Ozkinay F. The missing “link”: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. Hum Genet 2014; 133: 29-39
• 31 Bui C, Huber C, Tuysuz B, Alanay Y, Bole-Feysot C, Leroy JG, Mortier G, Nitschke P, Munnich A, Cormier-Daire V. XYLT1 mutations in Desbuquois dysplasia type 2. Am J Hum Genet 2014; 94: 405-414
• 32 Schwartz NB, Domowicz M. Proteoglycans in brain development. Glycoconj J 2004; 21: 329-341
• 33 Schwartz NB, Domowicz M. Chondrodysplasias due to proteoglycan defects. Glycobiology 2002; 12: 57R-68R
• 34 van Koningsbruggen S, Knoester H, Bakx R, Mook O, Knegt L, Cobben JM. Complete and partial XYLT1 deletion in a patient with neonatal short limb skeletal dysplasia. Am J Med Genet A 2016; 170A: 510-514
• 35 Jamsheer A, Olech EM, Kozlowski K, Niedziela M, Sowinska-Seidler A, Obara-Moszynska M, Latos-Bielenska A, Karczewski M, Zemojtel T. Exome sequencing reveals two novel compound heterozygous XYLT1 mutations in a Polish patient with Desbuquois dysplasia type 2 and growth hormone deficiency. J Hum Genet 2016; 61: 577-583
• 36 Schmidt H, Rudolph G, Hergersberg M, Schneider K, Moradi S, Meitinger T. Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred–a possible new syndrome. Clin Genet 2001; 59: 99-105
• 37 Rudolph G, Kalpadakis P, Bettecken T, Lichtner P, Haritoglou C, Hergersberg M, Meitinger T, Schmidt H. Spondylo-ocular syndrome: a new entity with crystalline lens malformation, cataract, retinal detachment, osteoporosis, and platyspondyly. Am J Ophthalmol 2003; 135: 681-687
• 38 Alanay Y, Superti-Furga A, Karel F, Tuncbilek E. Spondylo-ocular syndrome: a new entity involving the eye and spine. Am J Med Genet A 2006; 140: 652-656
• 39 Lu Q, Hasty P, Shur BD. Targeted mutation in beta1,4-galactosyltransferase leads to pituitary insufficiency and neonatal lethality. Develop Biol 1997; 181: 257-267
• 40 Guo MH, Stoler J, Lui J, Nilsson O, Bianchi DW, Hirschhorn JN, Dauber A. Redefining the progeroid form of Ehlers-Danlos syndrome: report of the fourth patient with B4GALT7 deficiency and review of the literature. Am J Med Genet A 2013; 161a: 2519-2527
• 41 Larsen LJ, Schottstaedt ER, Bost FC. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 1950; 37: 574-581
• 42 Payet G. Dwarfism and hyperlaxity, facial dysmorphism and multiple dislocations. Larsen’s syndrome?. Arch Fr Pediatr 1975; 32: 601-607
• 43 Hernandez A, Aguirre-Negrete MG, Ramirez-Soltero S, Gonzalez-Mendoza A, Martinez y Martinez R, Velazquez-Cabrera A, Cantu JM. A distinct variant of the Ehlers-Danlos syndrome. Clin Genet 1979; 16: 335-339
• 44 Bonaventure J, Lasselin C, Mellier J, Cohen-Solal L, Maroteaux P. Linkage studies of four fibrillar collagen genes in three pedigrees with Larsen-like syndrome. J Med Genet 1992; 29: 465-470
• 45 Kresse H, Rosthoj S, Quentin E, Hollmann J, Glossl J, Okada S, Tonnesen T. Glycosaminoglycan-free small proteoglycan core protein is secreted by fibroblasts from a patient with a syndrome resembling progeroid. Am J Hum Genet 1987; 41: 436-453
• 46 Almeida R, Levery SB, Mandel U, Kresse H, Schwientek T, Bennett EP, Clausen H. Cloning and expression of a proteoglycan UDP-galactose:beta-xylose beta1,4-galactosyltransferase I. A seventh member of the human beta4-galactosyltransferase gene family. J Biol Chem 1999; 274: 26165-26171
• 47 Okajima T, Fukumoto S, Furukawa K, Urano T. Molecular basis for the progeroid variant of Ehlers-Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene. J Biol Chem 1999; 274: 28841-28844
• 48 Quentin E, Gladen A, Roden L, Kresse H. A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: galactosyltransferase I deficiency in fibroblasts from a patient with a progeroid syndrome. Proc Natl Acad Sci U S A 1990; 87: 1342-1346
• 49 Seidler DG, Faiyaz-Ul-Haque M, Hansen U, Yip GW, Zaidi SH, Teebi AS, Kiesel L, Gotte M. Defective glycosylation of decorin and biglycan, altered collagen structure, and abnormal phenotype of the skin fibroblasts of an Ehlers-Danlos syndrome patient carrying the novel Arg270Cys substitution in galactosyltransferase I (beta4GalT-7). J Mol Med (Berl) 2006; 84: 583-594
• 50 Hernandez A, Aguirre-Negrete MG, Liparoli JC, Cantu JM. Third case of a distinct variant of the Ehlers-Danlos Syndrome (EDS). Clin Genet 1981; 20: 222-224
• 51 Hernandez A, Aguirre-Negrete MG, Gonzalez-Flores S, Reynoso-Luna MC, Fragoso R, Nazara Z, Tapia-Arizmendi G, Cantu JM. Ehlers-Danlos features with progeroid facies and mild mental retardation. Further delineation of the syndrome. Clin Genet 1986; 30: 456-461
• 52 Cartault F, Munier P, Jacquemont ML, Vellayoudom J, Doray B, Payet C, Randrianaivo H, Laville JM, Munnich A, Cormier-Daire V. Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome. Eur J Hum Genet 2015; 23: 49-53
• 53 Rahuel-Clermont S, Daligault F, Piet MH, Gulberti S, Netter P, Branlant G, Magdalou J, Lattard V. Biochemical and thermodynamic characterization of mutated beta1,4-galactosyltransferase 7 involved in the progeroid form of the Ehlers-Danlos syndrome. Biochem J 2010; 432: 303-311
• 54 Bui C, Talhaoui I, Chabel M, Mulliert G, Coughtrie MW, Ouzzine M, Fournel-Gigleux S. Molecular characterization of beta1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS). FEBS Lett 2010; 584: 3962-3968
• 55 Gotte M, Spillmann D, Yip GW, Versteeg E, Echtermeyer FG, van Kuppevelt TH, Kiesel L. Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (beta4GalT-7) deficient form of Ehlers-Danlos syndrome. Hum Mol Genet 2008; 17: 996-1009
• 56 Salter CG, Davies JH, Moon RJ, Fairhurst J, Bunyan D. Study DDD, Foulds N. Further defining the phenotypic spectrum of B4GALT7 mutations. Am J Med Genet A 2016; 170: 1556-1563
• 57 Cole SE, Mao MS, Johnston SH, Vogt TF. Identification, expression analysis, and mapping of B3galt6, a putative galactosyl transferase gene with similarity to Drosophila brainiac. Mamm Genom 2001; 12: 177-179
• 58 Bai X, Zhou D, Brown JR, Crawford BE, Hennet T, Esko JD. Biosynthesis of the linkage region of glycosaminoglycans: cloning and activity of galactosyltransferase II, the sixth member of the beta 1,3-galactosyltransferase family (beta 3GalT6). J Biol Chem 2001; 276: 48189-48195
• 59 Ueyama M, Takemae H, Ohmae Y, Yoshida H, Toyoda H, Ueda R, Nishihara S. Functional analysis of proteoglycan galactosyltransferase II RNA interference mutant flies. J Biol Chem 2008; 283: 6076-6084
• 60 Hwang HY, Olson SK, Brown JR, Esko JD, Horvitz HR. The Caenorhabditis elegans genes sqv-2 and sqv-6, which are required for vulval morphogenesis, encode glycosaminoglycan galactosyltransferase II and xylosyltransferase. J Biol Chem 2003; 278: 11735-11738
• 61 Malfait F, Kariminejad A, Van Damme T, Gauche C, Syx D, Merhi-Soussi F, Gulberti S, Symoens S, Vanhauwaert S, Willaert A, Bozorgmehr B, Kariminejad MH, Ebrahimiadib N, Hausser I, Huysseune A, Fournel-Gigleux S, De Paepe A. Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder. Am J Hum Genet 2013; 92: 935-945
• 62 Zhou D, Dinter A, Gutierrez Gallego R, Kamerling JP, Vliegenthart JF, Berger EG, Hennet T. A beta-1,3-N-acetylglucosaminyltransferase with poly-N-acetyllactosamine synthase activity is structurally related to beta-1,3-galactosyltransferases. Proc Natl Acad Sci USA 1999; 96: 406-411
• 63 Nakajima M, Mizumoto S, Miyake N, Kogawa R, Iida A, Ito H, Kitoh H, Hirayama A, Mitsubuchi H, Miyazaki O, Kosaki R, Horikawa R, Lai A, Mendoza-Londono R, Dupuis L, Chitayat D, Howard A, Leal GF, Cavalcanti D, Tsurusaki Y, Saitsu H, Watanabe S, Lausch E, Unger S, Bonafe L, Ohashi H, Superti-Furga A, Matsumoto N, Sugahara K, Nishimura G, Ikegawa S. Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am J Hum Genet 2013; 92: 927-934
• 64 Sellars EA, Bosanko KA, Lepard T, Garnica A, Schaefer GB. A newborn with complex skeletal abnormalities, joint contractures, and bilateral corneal clouding with sclerocornea. Seminars Pediatr Neurol 2014; 21: 84-87
• 65 Vorster AA, Beighton P, Ramesar RS. Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families. Clin Genet 2015; 87: 492-495
• 66 Alazami AM, Al-Qattan SM, Faqeih E, Alhashem A, Alshammari M, Alzahrani F, Al-Dosari MS, Patel N, Alsagheir A, Binabbas B, Alzaidan H, Alsiddiky A, Alharbi N, Alfadhel M, Kentab A, Daza RM, Kircher M, Shendure J, Hashem M, Alshahrani S, Rahbeeni Z, Khalifa O, Shaheen R, Alkuraya FS. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue. Human Genet 2016; 135: 525-540
• 67 Elenius V, Gotte M, Reizes O, Elenius K, Bernfield M. Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. The J Biol Chem 2004; 279: 41928-41935
• 68 Zhou Z, Wang J, Cao R, Morita H, Soininen R, Chan KM, Liu B, Cao Y, Tryggvason K. Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res 2004; 64: 4699-4702
• 69 Holmborn K, Habicher J, Kasza Z, Eriksson AS, Filipek-Gorniok B, Gopal S, Couchman JR, Ahlberg PE, Wiweger M, Spillmann D, Kreuger J, Ledin J. On the roles and regulation of chondroitin sulfate and heparan sulfate in zebrafish pharyngeal cartilage morphogenesis. J Biol Chem 2012; 287: 33905-33916
• 70 Izumikawa T, Kanagawa N, Watamoto Y, Okada M, Saeki M, Sakano M, Sugahara K, Sugihara K, Asano M, Kitagawa H. Impairment of embryonic cell division and glycosaminoglycan biosynthesis in glucuronyltransferase-I-deficient mice. J Biol Chem 2010; 285: 12190-12196
• 71 Baasanjav S, Al-Gazali L, Hashiguchi T, Mizumoto S, Fischer B, Horn D, Seelow D, Ali BR, Aziz SA, Langer R, Saleh AA, Becker C, Nurnberg G, Cantagrel V, Gleeson JG, Gomez D, Michel JB, Stricker S, Lindner TH, Nurnberg P, Sugahara K, Mundlos S, Hoffmann K. Faulty initiation of proteoglycan synthesis causes cardiac and joint defects. Am J Hum Genet 2011; 89: 15-27
• 72 von Oettingen JE, Tan WH, Dauber A. Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5-year-old boy-report of the second family with B3GAT3 mutation and expansion of the phenotype. Am J Med Genet A 2014; 164a: 1580-1586
• 73 Budde BS, Mizumoto S, Kogawa R, Becker C, Altmuller J, Thiele H, Ruschendorf F, Toliat MR, Kaleschke G, Hammerle JM, Hohne W, Sugahara K, Nurnberg P, Kennerknecht I. Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3. Hum Genet 2015; 134: 691-704
• 74 Jones KL, Schwarze U, Adam MP, Byers PH, Mefford HC. A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes. Am J Med Genet A 2015; 167A: 2691-2696
• 75 Faiyaz-Ul-Haque M, Zaidi SH, Al-Ali M, Al-Mureikhi MS, Kennedy S, Al-Thani G, Tsui LC, Teebi AS. A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type. Am J Med Genet A 2004; 128a: 39-45
• 76 Arunrut T, Sabbadini M, Jain M, Machol K, Scaglia F, Slavotinek A. Corneal clouding, cataract, and colobomas with a novel missense mutation in B4GALT7-a review of eye anomalies in the linkeropathy syndromes. Am J Med Genet A 2016; 170: 2711-2718