Novel RPL13 variants and variable clinical expressivity in a human ribosomopathy with spondyloepimetaphyseal dysplasia

Costantini, A., Alm, J.J., Tonelli, F., Valta, H., Huber, C., Tran, A.N., Daponte, V., Kirova, N., Kwon, Y.U., Bae, J.Y., Chung, W.Y., Tan, S., Sznajer, Y., Nishimura, G., Näreoja, T., Warren, A.J., Cormier-Daire, V., Kim, O.H., Forlino, A., Cho, T.J., Mäkitie, O.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research   36(2): 283-297 (Journal)
Registered Authors
CRISPR-Cas9, RPL13, incomplete penetrance, ribosomopathy, spondyloepimetaphyseal dysplasia, variable expressivity, zebrafish
MeSH Terms
  • Animals
  • Biological Variation, Population
  • Humans
  • Neoplasm Proteins
  • Osteochondrodysplasias*/diagnostic imaging
  • Osteochondrodysplasias*/genetics
  • Pedigree
  • Ribosomal Proteins/genetics
  • Spine
  • Zebrafish*/genetics
32916022 Full text @ J. Bone Miner. Res.
Osteochondrodysplasias are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with spondyloepimetaphyseal dysplasia (SEMD) in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient-derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation-positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR-Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD-RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. This article is protected by copyright. All rights reserved.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes