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.

Exploring lithium’s transcriptional mechanisms of action in bipolar disorder: a multi-step study

“…Only RPS23 was significantly differentially expressed in brain samples from BD subjects, but the effect was in the same direction as the effect of lithium, which is inconsistent with what one would expect if this gene was a mediating factor in lithium's therapeutic effects. RPS23, ribosomal protein S23, encodes a protein component of the small subunit of the ribosomal complex, and has been implicated in several developmental disorders [67]. DE analysis in human brain samples also revealed a suggestive finding in the GRIN2A gene, which had reduced expression in BD patients (Fig.…”

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

“…Two distinct missense mutations of RPS23 were found in two unrelated individuals with microcephaly, hearing loss, growth deficits, and dysmorphic features (Paolini et al . ). In addition, one patient presented ID/ASD.…”

“…Indeed, both mutations (R67K and Phe120Ile) affected ribosomal biogenesis reducing supply of the 40S SSU (Paolini et al . ). However, at least with one of those mutants (R67K from the ID/ASD case) general protein synthesis was unaffected and there was no deficit in cell proliferation (Paolini et al .…”

“…However, at least with one of those mutants (R67K from the ID/ASD case) general protein synthesis was unaffected and there was no deficit in cell proliferation (Paolini et al . ). These findings suggest ability of the mutant RPS23 to mediate translation.…”

How Ribosomes Translate Cancer

“…Alternatively, specialized composition of ribosomes in hematopoietic lineages might make these cells more vulnerable (14). Yet another potential explanation proposed for heterozygous defects could be that the balance between expression of the wild type and mutant protein might differ between tissues (183). Eventually however, the same cells gain a hyperproliferative phenotype.…”