TY - JOUR
T1 - A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism
AU - Paolini, Nahuel A.
AU - Attwood, Martin
AU - Sondalle, Samuel B.
AU - Vieira, Carolina Marques Dos Santos
AU - van Adrichem, Anita M.
AU - di Summa, Franca M.
AU - O'Donohue, Marie-Françoise
AU - Gleizes, Pierre-Emmanuel
AU - Rachuri, Swaksha
AU - Briggs, Joseph W.
AU - Fischer, Roman
AU - Ratcliffe, Peter J.
AU - Wlodarski, Marcin W.
AU - Houtkooper, Riekelt H.
AU - von Lindern, Marieke
AU - Kuijpers, Taco W.
AU - Dinman, Jonathan D.
AU - Baserga, Susan J.
AU - Cockman, Matthew E.
AU - MacInnes, Alyson W.
PY - 2017
Y1 - 2017
N2 - 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 poly some 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
AB - 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 poly some 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
U2 - https://doi.org/10.1016/j.ajhg.2017.01.034
DO - https://doi.org/10.1016/j.ajhg.2017.01.034
M3 - Article
C2 - 28257692
SN - 0002-9297
VL - 100
SP - 506
EP - 522
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -