title: Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders.
abstract: Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Ryo
authors.initials: R
authors.lastname: Kogawa
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.forename: Hironori
authors.initials: H
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitoh
authors.forename: Aya
authors.initials: A
authors.lastname: Hirayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsubuchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Miyazaki
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.forename: Angeline
authors.initials: A
authors.lastname: Lai
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.forename: Lucie
authors.initials: L
authors.lastname: Dupuis
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Andrew
authors.initials: A
authors.lastname: Howard
authors.forename: Gabriela F
authors.initials: GF
authors.lastname: Leal
authors.forename: Denise
authors.initials: D
authors.lastname: Cavalcanti
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Watanabe
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics*; D056726:Genetic Association Studies; D006025:Glycosaminoglycans / Q000096:biosynthesis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007593:Joint Instability / Q000201:enzymology / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000201:enzymology / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D006025:Glycosaminoglycans; C425302:B3GALT6 protein, human; D005700:Galactosyltransferases