A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism.

Autor:	Paolini NA; Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands., Attwood M; Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK., Sondalle SB; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA., Vieira CMDS; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA., van Adrichem AM; Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands., di Summa FM; Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands., O'Donohue MF; LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, 31000 Toulouse, France., Gleizes PE; LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, 31000 Toulouse, France., Rachuri S; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA., Briggs JW; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA., Fischer R; Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK., Ratcliffe PJ; Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK., Wlodarski MW; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Houtkooper RH; Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands., von Lindern M; Department of Hematopoiesis, Sanquin, and Landsteiner Laboratory, AMC/UvA, 1066 CX Amsterdam, the Netherlands., Kuijpers TW; Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands., Dinman JD; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA., Baserga SJ; Department of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA., Cockman ME; Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK., MacInnes AW; 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.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2017 Mar 02; Vol. 100 (3), pp. 506-522.
DOI:	10.1016/j.ajhg.2017.01.034
Abstrakt:	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. (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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