A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism

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 mic...

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Bibliographic Details
Published in:	American journal of human genetics Vol. 100; no. 3; pp. 506 - 522
Main Authors:	Paolini, Nahuel A., Attwood, Martin, Sondalle, Samuel B., Vieira, Carolina Marques dos Santos, van Adrichem, Anita M., di Summa, Franca M., O’Donohue, Marie-Françoise, Gleizes, Pierre-Emmanuel, Rachuri, Swaksha, Briggs, Joseph W., Fischer, Roman, Ratcliffe, Peter J., Wlodarski, Marcin W., Houtkooper, Riekelt H., von Lindern, Marieke, Kuijpers, Taco W., Dinman, Jonathan D., Baserga, Susan J., Cockman, Matthew E., MacInnes, Alyson W.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 02-03-2017 Cell Press Elsevier (Cell Press) Elsevier
Subjects:	Autism Spectrum Disorder - genetics Biochemistry, Molecular Biology Carrier Proteins - genetics Cells Cells, Cultured Child Child, Preschool Codon - genetics Deformities Developmental Disabilities - genetics Exome Female Fibroblasts - cytology Fibroblasts - metabolism Genes Genetic disorders Genetic Variation Genetics Genomics Hearing Loss - genetics Human genetics Humans Intellectual Disability - genetics Life Sciences Male Microcephaly - genetics Mutation Mutation, Missense Nuclear Proteins - genetics Oxidative Stress Protein Biosynthesis - genetics Ribonucleic acid Ribosomal Proteins - genetics Ribosomes - genetics RNA Sequence Alignment Sequence Analysis, DNA
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC5339345 These authors contributed equally to this work
ISSN:	0002-9297 1537-6605
DOI:	10.1016/j.ajhg.2017.01.034