Mutations in Hcfc1 and Ronin Result in an Inborn Error of Cobalamin Metabolism and Ribosomopathy

Authors

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

Publication Date

1-10-2022

Journal

Nature Communications

DOI

10.1038/s41467-021-27759-7

PMID

35013307

PMCID

PMC8748873

PubMedCentral® Posted Date

1-10-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Amino Acid Metabolism, Inborn Errors, Animals, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Homocystinuria, Host Cell Factor C1, Humans, Male, Mice, Mice, Knockout, Mutation, Organelle Biogenesis, Oxidoreductases, Protein Biosynthesis, Protein Subunits, Repressor Proteins, Ribosomal Proteins, Ribosomes, Vitamin B 12, Vitamin B 12 Deficiency, Disease model, Gene expression, Ribosome

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.

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