[en] Bi-allelic variants in CHTS-14, encoding dermatan 4-O sulfotransferase-1(D4ST-1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures and developmental abnormalities. Recently, the identification of bi-allelic variants in DSE, encoding dermatan-sulfate epimerase-1(DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity of this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondoitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and a second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of a dermal DS protoglycan decorin is impaired in fibroblasts from D4ST1, as well as DS-epi1-deficient patients. However, D4ST1-deficiency, decorin GAG is completely replaced by CS, whereas in DS-epi1-deficency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation and connective tissue integrity.
Research Center/Unit :
Center for Medical Genetics, Ghent University Hospital
Disciplines :
Human health sciences: Multidisciplinary, general & others
Author, co-author :
Syx, Delfien; Ghent University Hospital, Belgium > Center of Medical Genetics
Van Damme, Tim; Ghent University Hospital, Belgium > Center of Medical genetics
Symoens, Sofie; Ghent University Hospital, Belgium > Center of Medical Genetics
Maiburg, Merel; University Medical Center Utrecht, The Netherlands > Department of Medical Genetics Utrecht
van de Laar, Ingrid; Erasmus Universiteit Rotterdam - EUR > Department of Clinical Genetics
Morton, Jenny; Birmingham Women's Hospital, United Kingdom > Clinical gentics Unit
Suri, Mohnish; Nottingham City Hospital, United Kingdom > Nottingham Clinical Genetics Service
Del Campo, Miguel; Hospital Vall'Hebron, Barcelona, Spain > Area de Genetica Clinica y Molecular
Hausser, Ingrid; University Clinic Heidelberg, Germany > Institute of Pathology
Hermanns-Lê, Trinh ; Université de Liège > Département des sciences cliniques > Dermatopathologie
De Paepe, Anne; Ghent University Hospital, Belgium > Center of Medical Genetics
Malfait, Fransiska; Ghent University Hospital, Belgium > Center of Medical Genetics
Language :
English
Title :
Genetic heterogeneity and clinical variability in musculocontractural ehlers-danlos syndrome caused by impaired dermatan sulfate biosynthesis
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nat Methods 7:248-249.
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. 1998. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 77:31-37.
Byers PH, Murray ML. 2014. Ehlers-Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. Matrix Biol 33:10-15.
De Paepe A, Malfait F. 2012. The Ehlers-Danlos syndrome, a disorder with many faces. Clin Genet 82:1-11.
Dündar M, Demiryilmaz F, Demiryilmaz I, Kumandas S, Erkilic K, Kendirci M, Tuncel M, Ozyazgan I, Tolmie JL. 1997. An autosomal recessive adducted thumb-club foot syndrome observed in Turkish cousins. Clin Genet 51:61-64.
Dündar M, Kurtoglu S, Elmas B, Demiryilmaz F, Candemir Z, Ozkul Y, Durak AC. 2001. A case with adducted thumb and club foot syndrome. Clin Dysmorphol 10:291-293.
Dündar M, Müller T, Zhang Q, Pan J, Steinmann B, Vodopiutz J, Gruber R, Sonoda T, Krabichler B, Utermann G, Baenziger JU, Zhang L, et al. 2009. Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome. Am J Hum Genet 85:873-882.
He L, Giri TK, Vicente CP, Tollefsen DM. 2008. Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II. Blood 111:4118-4125.
Janecke AR, Baenziger JU, Müller T, Dündar M. 2011. Loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, dermatan sulfate-deficient adducted thumb-clubfoot syndrome. Hum Mutat 32:484-485.
Janecke AR, Unsinn K, Kreczy A, Baldissera I, Gassner I, Neu N, Utermann G, Müller T. 2001. Adducted thumb-club foot syndrome in sibs of a consanguineous Austrian family. J Med Genet 38:265-269.
Kosho T. 2013. Discovery and delineation of dermatan 4-O-sulfotransferase-1 (D4ST1)-deficient Ehlers-Danlos syndrome. Current genetics in dermatology. Rijeka: Intech. p 73-86.
Kosho T, Miyake N, Hatamochi A, Takahashi J, Kato H, Miyahara T, Igawa Y, Yasui H, Ishida T, Ono K, Kosuda T, Inoue A, et al. 2010. A new Ehlers-Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. Am J Med Genet A 152A:1333-1346.
Kosho T, Miyake N, Mizumoto S, Hatamochi A, Fukushima Y, Yamada S, Sugahara K, Matsumoto N. 2011. A response to: loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, dermatan sulfate-deficient Adducted Thumb-Clubfoot Syndrome. Which name is appropriate, Adducted Thumb-Clubfoot Syndrome or Ehlers-Danlos syndrome? Hum Mutat 32:1507-1509.
Kosho T, Mizumoto S, Sugahara K. 2014. Carbohydrate (N-acetylgalactosamine 4-O) sulfotransferase 14 (CHST14). Handbook of glycosyltransferases and related genes. Tokyo: Springer Japan. p 1135-1148.
Kosho T, Takahashi J, Ohashi H, Nishimura G, Kato H, Fukushima Y. 2005. Ehlers-Danlos syndrome type VIB with characteristic facies, decreased curvatures of the spinal column, and joint contractures in two unrelated girls. Am J Med Genet A 138A:282-287.
Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081.
Kusche-Gullberg M, Kjellén L. 2003. Sulfotransferases in glycosaminoglycan biosynthesis. Curr Opin Struct Biol 13:605-611.
Maccarana M, Kalamajski S, Kongsgaard M, Magnusson SP, Oldberg A, Malmström A. 2009. Dermatan sulfate epimerase 1-deficient mice have reduced content and changed distribution of iduronic acids in dermatan sulfate and an altered collagen structure in skin. Mol Cell Biol 29:5517-5528.
Malfait F, Syx D, Vlummens P, Symoens S, Nampoothiri S, Hermanns-Lê T, Van Laer L, De Paepe A. 2010. Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat 31:1233-1239.
Malmström A, Bartolini B, Thelin MA, Pacheco B, Maccarana M. 2012. Iduronic acid in chondroitin/dermatan sulfate: biosynthesis and biological function. J Histochem Cytochem 60:916-925.
Mendoza-Londono R, Chitayat D, Kahr WHA, Hinek A, Blaser S, Dupuis L, Goh E, Badilla-Porras R, Howard A, Mittaz L, Superti-Furga A, Unger S, et al. 2012. Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am J Med Genet A 158A:1344-1354.
Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Nagashima Y, Arai E, Takahashi K, Kawamura R, Wakui K, Takahashi J, Kato H, et al. 2010. Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum Mutat 31:966-974.
Müller T, Mizumoto S, Suresh I, Komatsu Y, Vodopiutz J, Dündar M, Straub V, Lingenhel A, Melmer A, Lechner S, Zschocke J, Sugahara K, et al. 2013. Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome. Hum Mol Genet 22:3761-3772.
Prydz K, Dalen KT. 2000. Synthesis and sorting of proteoglycans. J Cell Sci 113(Pt 2):193-205.
Schmidt G, Hausser H, Kresse H. 1991. Interaction of the small proteoglycan decorin with fibronectin. Involvement of the sequence NKISK of the core protein. Biochem J 280 (Pt 2):411-414.
Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. 2010. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575-576.
Shimizu K, Okamoto N, Miyake N, Taira K, Sato Y, Matsuda K, Akimaru N, Ohashi H, Wakui K, Fukushima Y, Matsumoto N, Kosho T. 2011. Delineation of dermatan 4-O-sulfotransferase 1 deficient Ehlers-Danlos syndrome: observation of two additional patients and comprehensive review of 20 reported patients. Am J Med Genet A 155A:1949-1958.
Silbert JE, Sugumaran G. 2002. Biosynthesis of chondroitin/dermatan sulfate. IUBMB Life 54:177-186.
Sonoda T, Kouno K. 2000. Two brothers with distal arthrogryposis, peculiar facial appearance, cleft palate, short stature, hydronephrosis, retentio testis, and normal intelligence: a new type of distal arthrogryposis? Am J Med Genet 91:280-285.
Taylor KR, Rudisill JA, Gallo RL. 2005. Structural and sequence motifs in dermatan sulfate for promoting fibroblast growth factor-2 (FGF-2) and FGF-7 activity. J Biol Chem 280:5300-5306.
Thelin MA, Bartolini B, Axelsson J, Gustafsson R, Tykesson E, Pera E, Oldberg A, Maccarana M, Malmström A. 2013. Biological functions of iduronic acid in chondroitin/dermatan sulfate. FEBS J 280:2431-2446.
Trowbridge JM, Gallo RL. 2002. Dermatan sulfate: new functions from an old glycosaminoglycan. Glycobiology 12:117R-25R.
Voermans NC, Kempers M, Lammens M, van Alfen N, Janssen MC, Bönnemann C, van Engelen BG, Hamel BC. 2012. Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation. Am J Med Genet A 158A:850-855.
Winters KA, Jiang Z, Xu W, Li S, Ammous Z, Jayakar P, Wierenga KJ. 2012. Re-assigned diagnosis of D4ST1-deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) after initial diagnosis of Marden-Walker syndrome. Am J Med Genet A 158A:2935-2940.
Yasui H, Adachi Y, Minami T, Ishida T, Kato Y, Imai K. 2003. Combination therapy of DDAVP and conjugated estrogens for a recurrent large subcutaneous hematoma in Ehlers-Danlos syndrome. Am J Hematol 72:71-72.
Zhang L, Müller T, Baenziger JU, Janecke AR. 2010. Congenital disorders of glycosylation with emphasis on loss of dermatan-4-sulfotransferase. Prog Mol Biol Transl Sci 93:289-307.
