King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

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, Ross A. Poché

Original languageEnglish
Article number134
JournalNature Communications
Issue number1
Early online date10 Jan 2022
Accepted/In press13 Dec 2021
E-pub ahead of print10 Jan 2022
PublishedDec 2022

Bibliographical note

Funding Information: We thank the Optical Imaging and Vital Microscopy (OIVM), the Genetically Engineered Mouse (GEM) and Mass Spectrometry Proteomics Core facilities at Baylor College of Medicine (BCM), the Baylor Genetics Biochemical Genetics Laboratory for their services, and Duke University School of Medicine for the use of the Sequencing and Genomic Technologies Shared Resource. The BCM Mass Spectrometry Proteomics Core is supported by the Dan L. Duncan Comprehensive Cancer Center NIH award (P30 CA125123) and CPRIT Core Facility Award (RP170005). This work was supported by the following grants from the National Institutes of Health (NIH): R01 EY024906 and R01 DE028298 to Ross Poché, T32 EY007102 to Graeme Mardon and T32 HL007676 to Susan Hamilton (supporting Tiffany Chern), R01 HL127717, R01 HL130804, R01 HL118761 to James Martin. Additional support was provided by the Vivian L. Smith Foundation, State of Texas funding, Fondation LeDucq Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01) to James Martin. The cartoons in Fig. 8 were created with (full subscription). Publisher Copyright: © 2022, The Author(s).

King's Authors


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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454