 |
Proteoglycans contain glycosaminoglycan (GAG) side chains, and play roles in regulating cell signal transductions and assembly of the extracellular matrix (1). GAGs forming proteoglycans are classified as chondroitin sulfate (CS), dermatan sulfate (DS), and heparan sulfate (HS). Details of the biosynthetic mechanisms, analyses of knockout mice, and congenital disorders of GAGs are referred to within other sections in this series. CS/DS/HS except for keratan sulfate is covalently attached to core proteins via a common linker-region tetrasaccharide, glucuronic acid–galactose–galactose–xylose–O– (GlcA-Gal-Gal-Xyl-O-). Pathogenic variants of these genes encoding glycosyltransferases involved in the biosynthesis of linker-region tetrasaccharides cause a congenital disorder, “proteoglycan linkeropathy”, characterized by skeletal, cutis, and heart anomalies (Table 1) (2-4). Proteoglycan linkeropathy was initially proposed by Dr. Shiro IKEGAWA (Riken), and it includes a wide range of clinical manifestations caused by defects in the biosynthesis of CS/DS/HS (5).
Pathogenic variants in Xyl-transferase-1 (XYLT1) cause Desbuquois dysplasia type 2, characterized by a short stature, severe pre- and postnatal growth retardation, a flat face with prominent eyes, the dislocation of large joints, and joint laxity (6-10). Pathogenic variants in XYLT2 cause spondyloocular syndrome, characterized by retinal detachment, amblyopia, nystagmus, hearing loss, heart septal defects, bone fragility, and mild learning difficulties (11-13). Distinct clinical manifestations differ between patients with mutations in XYLT1 and XYLT2, suggesting divergences in their spatiotemporal expressions and/or that core proteins recognized by XYLT1 are distinct from XYLT2.
Pathogenic variants in B4GALT7 encoding Gal-transferase-I (GalT-I) cause Ehlers-Danlos syndrome (EDS) spondylodysplastic type 1 (14-19). Clinical symptoms of patients include an aged appearance, craniofacial dysmorphism, hypermobile joints, generalized osteopenia, a short stature, hypotonic muscles, defective wound healing, radioulnar synostosis, scoliosis, and severe hypermetropia.
Pathogenic variants in B3GALT6 encoding GalT-II cause EDS spondylodysplastic type 2 or spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1) (5, 20-22). SEMD-JL1 is characterized by joint laxity, kyphoscoliosis, clubfeet, hip dislocation, elbow contracture, platyspondyly, and craniofacial dysmorphisms including a small mandible with cleft palate, prominent eyes, and a long upper lip. Recombinant B3GALT6-mutant enzymes related to SEMD-JL1 markedly reduced Gal-transferase activity (5). In addition, the amount of HS but not CS/DS in cultured lymphoblastoid cells from patients with SEMD-JL1 is lower than that of normal subjects (5). However, CS/DS as well as HS are decreased in skin fibroblast cultures from patients with spondylodysplastic EDS compared with those from control cells (20). Different B3GALT6 gene mutations lead to diverse symptoms of spondylodysplastic EDS and SEMD-JL1. This is because the amount and chain length of CS/DS/HS vary dependent on the respective mutations.
The pathogenic variants in B3GAT3 encoding GlcA-transferase-I (GlcAT-I) cause multiple joint dislocations, a short stature, and craniofacial dysmorphism with or without congenital heart defects (23-28). This disorder is variously characterized by a bicuspid aortic valve in the heart, elbow dislocation, kyphoscoliosis, a short stature, severe phenotype of osteoporosis, hypotonia, joint laxity and contracture, cutis laxa, myopia, glaucoma, craniosynostosis, radioulnar or radiohumeral synostosis, and midface hypoplasia. Different genetic mutation sites in B3GAT3 can give rise to diverse symptoms, likely due to varying levels of CS, DS, and HS in respective mutations. Further studies are needed to understand the mechanisms that determine the different phenotypic effects of mutations in the single gene, B3GAT3. GlcAT-I activity as well as levels of CS/DS/HS in patients’ cells were significantly lower than those in healthy controls (23, 25, 26).
The pathogenic variants in FAM20B encoding Xyl 2-O-kinase cause neonatal short limb dysplasia resembling Desbuquois dysplasia (29). Clinical symptoms are characterized by mid-face hypoplasia, thoracic hypoplasia with respiratory failure, a very short stature with mesomelic shortening of the limbs, multiple dislocations of large joints, and preaxial digital hypoplasia as well as syndactyly.
Table 1. Proteoglycan linkeropathy of GAG-protein linker region tetrasaccharide deficiency
| Coding genes | Enzymes | Chromosomal location | MIM* number | Human genetic disorders |
| XYLT1 | XylT
| 16p12.3 | 615777
608124
| Desbuquios dysplasia type 2; Short stature syndrome |
| XYLT2 | XylT | 17q21.33 | 605822
608125
| Spondyloocular syndrome |
| B4GALT7 | GalT-I | 5q35.3 | 130070
604327
| Ehlers-Danlos syndrome spondylodysplastic type 1; Ehlers-Danlos syndrome progeroid type 1;
Ehlers-Danlos syndrome with short stature and limb anomalies; Larsen of Reunion Island syndrome
|
| B3GALT6 | GalT-II | 1p36.33 | 271640
609465
615349
615291
| Ehlers-Danlos syndrome spondylodysplastic type 2;
Ehlers-Danlos syndrome progeroid type 2; Spondyloepimetaphyseal dysplasia with joint laxity type 1; Al-Gazali syndrome
|
| B3GAT3 | GlcAT-I | 11q12.3 | 245600
606374
| Multiple joint dislocations, short stature, craniofacial dysmorphism with or without congenital heart defects; Larsen-like syndrome B3GAT3 type;
B3GAT3-related disorder with dislocation and congenital heart defects; with cutis laxa and bone fragility; with the intermediate phenotype; or with craniosynostosis and bone fragility
|
| FAM20B | Xyl-kinase | 1q25.2 | 611063
| Neonatal short limb dysplasia resembling Desbuquois dysplasia |
* MIM, Mendelian inheritance in man
Table 2. References for proteoglycan linkeropathy
|
Gene |
Original papers
|
| XYLT1 |
(6) 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. 94, 405-414, 2014
(7) Schreml J, Durmaz B, Cogulu O, Keupp K, Beleggia F, Pohl E, Milz E, Coker M, Ucar SK, Nürnberg G, Nürnberg P, Kuhn J, Ozkinay F: The missing "link": an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. Hum. Genet. 133, 29-39, 2014
(8) Silveira C, Leal GF, Cavalcanti DP: Desbuquois dysplasia type II in a patient with a homozygous mutation in XYLT1 and new unusual findings. Am. J. Med. Genet. A 170, 3043-3047, 2016
(9) Al-Jezawi NK, Ali BR, Al-Gazali L: Endoplasmic reticulum retention of xylosyltransferase 1 (XYLT1) mutants underlying Desbuquois dysplasia type II. Am. J. Med. Genet. A 173, 1773-1781, 2017
(10) Guo L, Elcioglu NH, Iida A, Demirkol YK, Aras S, Matsumoto N, Nishimura G, Miyake N, Ikegawa S: Novel and recurrent XYLT1 mutations in two Turkish families with Desbuquois dysplasia, type 2. J. Hum. Genet. 62, 447-451, 2017 |
| XYLT2 |
(11) 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. 96, 971-978, 2015
(12) Taylan F, Yavaş Abalı Z, Jäntti N, Güneş N, Darendeliler F, Baş F, Poyrazoğlu Ş, Tamçelik N, Tüysüz B, Mäkitie O: Two novel mutations in XYLT2 cause spondyloocular syndrome. Am. J. Med. Genet. A. 173, 3195-3200, 2017
(13) Umair M, Eckstein G, Rudolph G, Strom T, Graf E, Hendig D, Hoover J, Alanay J, Meitinger T, Schmidt H, Ahmad W: Homozygous XYLT2 variants as a cause of spondyloocular syndrome. Clin. Genet. 93, 913-918, 2017
|
| B4GALT7 |
(14) Okajima T, Yoshida K, Kondo T, Furukawa K: Human homolog of Caenorhabditis elegans sqv-3 gene is galactosyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans. J. Biol. Chem. 274, 22915-22918, 1999
(15) 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. 274, 26165-26171, 1999
(16) 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. 161A, 2519-2527, 2013
(17) Götte 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. 17, 996-1009, 2008
(18) Salter CG, Davies JH, Moon RJ, Fairhurst J, Bunyan D; DDD Study; Foulds N: Further defining the phenotypic spectrum of B4GALT7 mutations. Am. J. Med. Genet. A 170, 1556-1563, 2016
(19) 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 170, 2711-2718, 2016
|
| B3GALT6
|
(5) 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, Bonafé 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. 92, 927-934, 2013
(20) 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. 92, 935-945, 2013
(21) Vorster AA, Beighton P, Ramesar RS: Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families. Clin. Genet. 87, 492-495, 2015
(22) 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. Hum. Genet. 135, 525-540, 2016 |
| B3GAT3 |
(23) 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, Nürnberg G, Cantagrel V, Gleeson JG, Gomez D, Michel JB, Stricker S, Lindner TH, Nürnberg P, Sugahara K, Mundlos S, Hoffmann K: Faulty initiation of proteoglycan synthesis causes cardiac and joint defects. Am. J. Hum. Genet. 89, 15-27, 2011
(24) 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 164A, 1580-1586, 2014
(25) Budde BS, Mizumoto S, Kogawa R, Becker C, Altmüller J, Thiele H, Rüschendorf F, Toliat MR, Kaleschke G, Hämmerle JM, Höhne W, Sugahara K, Nürnberg 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. 134, 691-704, 2015
(26) Job F, Mizumoto S, Smith L, Couser N, Brazil A, Saal H, Patterson M, Gibson MI, Soden S, Miller N, Thiffault I, Saunders C, Yamada S, Hoffmann K, Sugahara K, Farrow E: Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype. BMC Med. Genet. 17, 86, 2016
(27) 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 167A, 2691-2696, 2015
(28) Yauy K, Tran Mau-Them F, Willems M, Coubes C, Blanchet P, Herlin C, Taleb Arrada I, Sanchez E, Faure JM, Le Gac MP, Prodhomme O, Boland A, Meyer V, Rivière JB, Duffourd Y, Deleuze JF, Guignard T, Captier G, Barat-Houari M, Genevieve D: B3GAT3-related disorder with craniosynostosis and bone fragility due to a unique mutation. Genet. Med. 20, 269-274, 2018
|
| FAM20B |
(29) Kuroda Y, Murakami H, Enomoto Y, Tsurusaki Y, Takahashi K, Mitsuzuka K, Ishimoto H, Nishimura G, Kurosawa K: A novel gene (FAM20B encoding glycosaminoglycan xylosylkinase) for neonatal short limb dysplasia resembling Desbuquois dysplasia. Clin. Genet. 95, 713-717, 2019
|
Shuji Mizumoto
(Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University)
| References |
| (1) |
Kjellén L, Lindahl U: Proteoglycans: structures and interactions. Annu. Rev. Biochem.60, 443-475, 1991 |
| (2) |
Mizumoto S: Defects in biosynthesis of glycosaminoglycans cause hereditary bone, skin, heart, immune, and neurological disorders. Trend. Glycosci. Glycotechnol.30, E67-E89, 2018 |
| (3) |
Mizumoto S, Yamada S: Congenital disorders caused by defects in anabolism of glycosaminoglycans. Trend. Glycosci. Glycotechnol.32, E45-E51, 2020 |
| (4) |
Mizumoto S, Yamada S: Congenital disorders of deficiency in glycosaminoglycan biosynthesis. Front. Genet. 12, 717535, 2021 |
| (5) |
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, Bonafé 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. 92, 927-934, 2013 |
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