npj Genomic Medicine (Nov 2023)

Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13

  • Prince Jacob,
  • Hillevi Lindelöf,
  • Cecilie F. Rustad,
  • Vernon Reid Sutton,
  • Shahida Moosa,
  • Prajna Udupa,
  • Anna Hammarsjö,
  • Gandham SriLakshmi Bhavani,
  • Dominyka Batkovskyte,
  • Kristian Tveten,
  • Ashwin Dalal,
  • Eva Horemuzova,
  • Ann Nordgren,
  • Emma Tham,
  • Hitesh Shah,
  • Else Merckoll,
  • Laura Orellana,
  • Gen Nishimura,
  • Katta M. Girisha,
  • Giedre Grigelioniene

DOI
https://doi.org/10.1038/s41525-023-00380-x
Journal volume & issue
Vol. 8, no. 1
pp. 1 – 10

Abstract

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Abstract Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2–64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants’ impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.