1. Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.
- Author
-
Chern T, Achilleos A, Tong X, Hill MC, Saltzman AB, Reineke LC, Chaudhury A, Dasgupta SK, Redhead Y, Watkins D, Neilson JR, Thiagarajan P, Green JBA, Malovannaya A, Martin JF, Rosenblatt DS, and Poché RA
- Subjects
- Amino Acid Metabolism, Inborn Errors metabolism, Amino Acid Metabolism, Inborn Errors pathology, Animals, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Homocystinuria metabolism, Homocystinuria pathology, Host Cell Factor C1 deficiency, Humans, Male, Mice, Mice, Knockout, Mutation, Organelle Biogenesis, Oxidoreductases deficiency, Protein Biosynthesis, Protein Subunits genetics, Protein Subunits metabolism, Repressor Proteins deficiency, Ribosomal Proteins genetics, Ribosomal Proteins metabolism, Ribosomes metabolism, Ribosomes pathology, Vitamin B 12 metabolism, Vitamin B 12 Deficiency metabolism, Vitamin B 12 Deficiency pathology, Amino Acid Metabolism, Inborn Errors genetics, Homocystinuria genetics, Host Cell Factor C1 genetics, Oxidoreductases genetics, Repressor Proteins genetics, Ribosomes genetics, Vitamin B 12 Deficiency genetics
- 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., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF