title: Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human.
abstract: Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein. Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate. The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis. Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shibata
authors.forename: Masaki
authors.initials: M
authors.lastname: Yanagishita
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Peter G
authors.initials: PG
authors.lastname: Nikkels
authors.forename: Minako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Kayoko
authors.initials: K
authors.lastname: Katsuyama
authors.forename: Hidenao
authors.initials: H
authors.lastname: Toyoda
authors.forename: Akiko
authors.initials: A
authors.lastname: Kinoshita-Toyoda
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ishida
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Isono
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sanai
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D002809:Chondroitin Sulfates / Q000096:biosynthesis*; D004838:Epiphyses / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D005147:Facial Bones / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D006801:Humans; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D033704:Nucleotide Transport Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D009004:Monosaccharide Transport Proteins; D033704:Nucleotide Transport Proteins; C425807:SLC35D1 protein, human; C526259:Slc35d1 protein, mouse; D002809:Chondroitin Sulfates