RRC ID 44437
Author 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.
Title Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders.
Journal Am J Hum Genet
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.
Volume 92(6)
Pages 927-34
Published 2013-6-6
DOI 10.1016/j.ajhg.2013.04.003
PII S0002-9297(13)00164-X
PMID 23664117
PMC PMC3675233
MeSH Abnormalities, Multiple / genetics* Adult Child Child, Preschool Female Galactosyltransferases / genetics* Genetic Association Studies Glycosaminoglycans / biosynthesis High-Throughput Nucleotide Sequencing Humans Joint Instability / enzymology Joint Instability / genetics* Male Mutation, Missense* Osteochondrodysplasias / enzymology Osteochondrodysplasias / genetics* Sequence Analysis, DNA
IF 10.502
Times Cited 69
Human and Animal Cells HeLa