RRM2B encodes the crucial p53-inducible ribonucleotide reductase small subunit 2 homolog (p53R2), which is required for DNA synthesis throughout the cell cycle. Mutations in this gene have been associated with a lethal mitochondrial depletion syndrome. Here we present the case of an infant with a novel homozygous p.Asn221Ser mutation in RRM2B who developed hypotonia, failure to thrive, sensorineural hearing loss, and severe metabolic lactic acidosis, ultimately progressing to death at 3 months of age. Through molecular modeling using the X-ray crystal structure of p53R2, we demonstrate that this mutation likely causes disruption of a highly conserved helix region of the protein by altering intramolecular interactions. This report expands our knowledge of potential pathogenic RRM2B mutations as well as our understanding of the molecular function of p53R2 and its role in the pathogenesis of mitochondrial DNA depletion.
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Penque, B. A., Su, L., Wang, J., Ji, W., Bale, A., Luh, F., Fulbright, R. K., Sarmast, U., Sega, A. G., Konstantino, M., Spencer-Manzon, M., Pierce, R., Yen, Y., & Lakhani, S. A. (認可的出版社/出版中). A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death. European Journal of Medical Genetics. https://doi.org/10.1016/j.ejmg.2018.11.008