title: Dysplastic spondylolysis is caused by mutations in the diastrophic dysplasia sulfate transporter gene.
abstract: Spondylolysis is a fracture in part of the vertebra with a reported prevalence of about 3-6% in the general population. Genetic etiology of this disorder remains unknown. The present study was aimed at identifying genomic mutations in patients with dysplastic spondylolysis as well as the potential pathogenesis of the abnormalities. Whole-exome sequencing and functional analysis were performed for patients with spondylolysis. We identified a novel heterozygous mutation (c.2286A > T; p.D673V) in the sulfate transporter gene SLC26A2 in five affected subjects of a Chinese family. Two additional mutations (e.g., c.1922A > G; p.H641R and g.18654T > C in the intron 1) in the gene were identified by screening a cohort of 30 unrelated patients with the disease. In situ hybridization analysis showed that SLC26A2 is abundantly expressed in the lumbosacral spine of the mouse embryo at day 14.5. Sulfate uptake activities in CHO cells transfected with mutant SLC26A2 were dramatically reduced compared with the wild type, confirming the pathogenicity of the two missense mutations. Further analysis of the gene-disease network revealed a convergent pathogenic network for the development of lumbosacral spine. To our knowledge, our findings provide the first identification of autosomal dominant SLC26A2 mutations in patients with dysplastic spondylolysis, suggesting a new clinical entity in the pathogenesis of chondrodysplasia involving lumbosacral spine. The analysis of the gene-disease network may shed new light on the study of patients with dysplastic spondylolysis and spondylolisthesis as well as high-risk individuals who are asymptomatic.
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China; tcai@mail.nih.gov zjluo@fmmu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
authors.affiliation: Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710000, China;
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100000, China;
authors.forename: Wanshi
authors.initials: W
authors.lastname: Cai
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China;
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China;
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China;
authors.forename: Jinchen
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710000, China;
authors.forename: Xueyu
authors.initials: X
authors.lastname: Hu
authors.affiliation: Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710000, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China;
authors.forename: Qianzhi
authors.initials: Q
authors.lastname: Shao
authors.affiliation: School of Stomatology, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China; Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100000, China;
authors.forename: Zhong Sheng
authors.initials: ZS
authors.lastname: Sun
authors.affiliation: Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710000, China; tcai@mail.nih.gov zjluo@fmmu.edu.cn.
authors.forename: Zhuo-Jing
authors.initials: ZJ
authors.lastname: Luo
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D027321:Anion Transport Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013169:Spondylolysis / Q000235:genetics* / Q000503:physiopathology; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters
keywords: dysplastic spondylolysis; lumbosacral spine; solute carrier family 26 sulfate transporter; spondylolisthesis; whole-exome sequencing