Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy

Tiffany Chern, Annita Achilleos (), Xuefei Tong, Matthew C. Hill, Alexander B. Saltzman, Lucas C. Reineke, Arindam Chaudhury, Swapan K. Dasgupta, Yushi Redhead, David Watkins, Joel R. Neilson, Perumal Thiagarajan, Jeremy B. A. Green, Anna Malovannaya, James F. Martin, David S. Rosenblatt and Ross A. Poché ()
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Tiffany Chern: Baylor College of Medicine
Annita Achilleos: Baylor College of Medicine
Xuefei Tong: Baylor College of Medicine
Matthew C. Hill: Baylor College of Medicine
Alexander B. Saltzman: Baylor College of Medicine
Lucas C. Reineke: Baylor College of Medicine
Arindam Chaudhury: Baylor College of Medicine
Swapan K. Dasgupta: Michael E. DeBakey Veterans Affairs Medical Center
Yushi Redhead: The Francis Crick Institute
David Watkins: McGill University Health Centre
Joel R. Neilson: Baylor College of Medicine
Perumal Thiagarajan: Michael E. DeBakey Veterans Affairs Medical Center
Jeremy B. A. Green: King’s College London
Anna Malovannaya: Baylor College of Medicine
James F. Martin: Baylor College of Medicine
David S. Rosenblatt: McGill University Health Centre
Ross A. Poché: Baylor College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.

Date: 2022
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DOI: 10.1038/s41467-021-27759-7

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