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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  cbl C, 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.

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