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

• Published in: Nature communications Vol. 13; no. 1; p. 134
• Main Authors: Chern, Tiffany, Achilleos, Annita, Tong, Xuefei, Hill, Matthew C., Saltzman, Alexander B., Reineke, Lucas C., Chaudhury, Arindam, Dasgupta, Swapan K., Redhead, Yushi, Watkins, David, Neilson, Joel R., Thiagarajan, Perumal, Green, Jeremy B. A., Malovannaya, Anna, Martin, James F., Rosenblatt, David S., Poché, Ross A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 14/19; 38/15; 38/35; 38/39; 38/88; 42/41; 45/90; 45/91; 59/57; 631/136/1425; 631/208/199; 631/337/574/1789; 64/60; 82/58; 82/80; Aciduria; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - metabolism; Amino Acid Metabolism, Inborn Errors - pathology; Animal models; Animals; Biosynthesis; Cyanocobalamin; Deregulation; Disease Models, Animal; Embryo, Mammalian; Errors; Evolution; Female; Gene expression; Gene Expression Regulation, Developmental; Genes; Homocystinuria; Homocystinuria - genetics; Homocystinuria - metabolism; Homocystinuria - pathology; Host Cell Factor C1 - deficiency; Host Cell Factor C1 - genetics; Humanities and Social Sciences; Humans; Inborn errors of metabolism; Male; Metabolism; Mice; Mice, Knockout; multidisciplinary; Mutation; Organelle Biogenesis; Oxidoreductases - deficiency; Oxidoreductases - genetics; Perturbation; Phenotypes; Protein Biosynthesis; Protein Subunits - genetics; Protein Subunits - metabolism; Repressor Proteins - deficiency; Repressor Proteins - genetics; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; Ribosomes - genetics; Ribosomes - metabolism; Ribosomes - pathology; Science; Science (multidisciplinary); Transcription; Vitamin B 12 - metabolism; Vitamin B 12 Deficiency - genetics; Vitamin B 12 Deficiency - metabolism; Vitamin B 12 Deficiency - pathology; Vitamin B12
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27759-7

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. Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.