Author
Listed:
- Tiffany Chern
(Baylor College of Medicine
Baylor College of Medicine)
- Annita Achilleos
(Baylor College of Medicine
University of Nicosia Medical School)
- Xuefei Tong
(Baylor College of Medicine)
- Matthew C. Hill
(Baylor College of Medicine
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
King’s College London)
- David Watkins
(McGill University Health Centre
McGill University Health Centre)
- Joel R. Neilson
(Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine)
- Perumal Thiagarajan
(Michael E. DeBakey Veterans Affairs Medical Center
Baylor College of Medicine)
- Jeremy B. A. Green
(King’s College London)
- Anna Malovannaya
(Baylor College of Medicine)
- James F. Martin
(Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine)
- David S. Rosenblatt
(McGill University Health Centre
McGill University Health Centre
McGill University)
- Ross A. Poché
(Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine)
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.
Suggested Citation
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 &, 2022.
"Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy,"
Nature Communications, Nature, vol. 13(1), pages 1-21, December.
Handle:
RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27759-7
DOI: 10.1038/s41467-021-27759-7
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