A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism

Am J Hum Genet. 2017 Mar 2;100(3):506-522. doi: 10.1016/j.ajhg.2017.01.034.

Nahuel A Paolini ¹, Martin Attwood ², Samuel B Sondalle ³, Carolina Marques Dos Santos Vieira ⁴, Anita M van Adrichem ⁵, Franca M di Summa ¹, Marie-Françoise O'Donohue ⁶, Pierre-Emmanuel Gleizes ⁶, Swaksha Rachuri ⁴, Joseph W Briggs ⁴, Roman Fischer ², Peter J Ratcliffe ², Marcin W Wlodarski ⁷, Riekelt H Houtkooper ⁵, Marieke von Lindern ¹, Taco W Kuijpers ⁸, Jonathan D Dinman ⁴, Susan J Baserga ⁹, Matthew E Cockman ², Alyson W MacInnes ¹⁰

Affiliations

1 Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands.
2 Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
3 Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
5 Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
6 LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
7 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
8 Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
9 Department of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
10 Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands; Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands. Electronic address: a.w.macinnes@amc.nl.

PMID: 28257692 DOI: 10.1016/j.ajhg.2017.01.034

Abstract

Ribosomal protein (RP) gene mutations, mostly associated with inherited or acquired bone marrow failure, are believed to drive disease by slowing the rate of protein synthesis. Here de novo missense mutations in the RPS23 gene, which codes for uS12, are reported in two unrelated individuals with microcephaly, hearing loss, and overlapping dysmorphic features. One individual additionally presents with intellectual disability and autism spectrum disorder. The amino acid substitutions lie in two highly conserved loop regions of uS12 with known roles in maintaining the accuracy of mRNA codon translation. Primary cells revealed one substitution severely impaired OGFOD1-dependent hydroxylation of a neighboring proline residue resulting in 40S ribosomal subunits that were blocked from polysome formation. The Other disrupted a predicted pi-pi stacking interaction between two phenylalanine residues leading to a destabilized uS12 that was poorly tolerated in 40S subunit biogenesis. Despite no evidence of a reduction in the rate of mRNA translation, these uS12 variants impaired the accuracy of mRNA translation and rendered cells highly sensitive to oxidative stress. These discoveries describe a ribosomopathy linked to uS12 and reveal mechanistic distinctions between RP gene mutations driving hematopoietic disease and those resulting in developmental disorders.

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