Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

PLoS One. 2016 Mar 14;11(3):e0150555. doi: 10.1371/journal.pone.0150555. eCollection 2016.


Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

MeSH terms

  • Adolescent
  • Cartilage / metabolism
  • Cartilage / pathology
  • Cell Differentiation / genetics
  • Child
  • Child, Preschool
  • Cytoskeletal Proteins
  • Female
  • Gene Expression Regulation
  • Genetic Diseases, Inborn / diagnostic imaging
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / metabolism
  • Humans
  • Male
  • Mutation*
  • Osteochondrodysplasias / diagnostic imaging
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / metabolism
  • Phenotype
  • Proteins / genetics*
  • Proteins / metabolism
  • Radiography
  • Retina / metabolism
  • Retina / pathology
  • Young Adult


  • CFAP410 protein, human
  • Cytoskeletal Proteins
  • Proteins

Supplementary concepts

  • Strudwick syndrome

Grants and funding

This work was funded by No. M15319, Japan Agency For Medical Research and Development,, to SI; No. 26893018, KAKENHI Grants-in-Aid for Scientific Research, Research Activity Start-up,, to KMN; No. 25293235, KAKENHI Grant-in-Aid for Scientific Research (B),, to N. Miyake; Takeda Science Foundation,, to ZW, N. Miyake, N. Matsumoto. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.