title: A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism.
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.
authors.affiliation: Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands.
authors.forename: Nahuel A
authors.initials: NA
authors.lastname: Paolini
authors.affiliation: Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Attwood
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Sondalle
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Carolina Marques Dos Santos
authors.initials: CMDS
authors.lastname: Vieira
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Anita M
authors.initials: AM
authors.lastname: van Adrichem
authors.affiliation: Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands.
authors.forename: Franca M
authors.initials: FM
authors.lastname: di Summa
authors.affiliation: LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: O'Donohue
authors.affiliation: LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Gleizes
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Swaksha
authors.initials: S
authors.lastname: Rachuri
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Briggs
authors.affiliation: Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.affiliation: Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Dinman
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Baserga
authors.affiliation: Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Cockman
authors.affiliation: 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.
authors.forename: Alyson W
authors.initials: AW
authors.lastname: MacInnes
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D014644:Genetic Variation; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D018384:Oxidative Stress; D014176:Protein Biosynthesis / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D003062:Codon; D009687:Nuclear Proteins; C548916:OGFOD1 protein, human; C484213:RPS23 protein, human; D012269:Ribosomal Proteins