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

Tiffany Chern,Alexander B Saltzman,Anna Malovannaya,Perumal Thiagarajan,Ross A Poché,Swapan K Dasgupta,David S Rosenblatt,Jeremy B A Green,Joel R Neilson,Lucas C Reineke,David Watkins,James F Martin,Yushi Redhead,Annita Achilleos,Xuefei Tong,Arindam Chaudhury,Matthew C Hill

doi:10.1038/s41467-021-27759-7

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.

Highlights

Combined methylmalonic acidemia and homocystinuria is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC)
These Hcfc1+/A115V females were crossed to wild type males on the same C57BL/6J genetic background, and we found that Hcfc1A115V/Y hemizygous male progeny were underrepresented by ~50% at weaning (Fig. 1f)
To better understand the pathophysiology of these diseases, we have generated Hcfc1A115V/Y and RoninF80L/F80L mouse models. These mutant mice exhibited the expected congenital homocystinuria and methylmalonic acidemia, which are the metabolic hallmarks of a cobalamin deficiency syndrome

Summary

Introduction

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). Cells from patients with this disorder do not correct cells from cblC in somatic cell complementation studies and are not a new complementation group, but rather cellular phenocopies of cblC Another patient having a cblX-like syndrome carried mutations in the gene encoding the transcription factor THAP Domain Containing 11 (THAP11— known as RONIN), which was initially identified as an embryonic stem cell (ESC) pluripotency factor[21,22]. To gain greater insight into the pathophysiology of these disorders, we generated mouse models carrying the same point mutations as the human patients (Hcfc1A115V/Y and RoninF80L/F80L) Phenotyping showed that both lines exhibit combined methylmalonic acidemia and homocystinuria and we observed CNS, hematological, and cardiac defects consistent with cblC patients. It was shown that, depending on whether a large or small subunit protein was deleted, the cell experiences an increase in proteins involved in proteasome-mediated degradation or ribosome biogenesis

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Conclusion