Scientist at the Baylor College of Medicine and collaborating institutions say their paper (“Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy”) in Nature Communications sheds new light into the complexity of vitamin B12 diseases. The researchers studied two rare inherited vitamin B12 conditions that affect the same gene but are clinically distinct from the most common genetic vitamin B12 disorder. This work suggested that, in addition to the gene affected in the common vitamin B12 disease, other genes also were affected, making a more complex syndrome. This study searched for those genes and their function.

Working with mouse models, the team found that the genes involved in the more complex forms of the condition not only cause the expected typical vitamin B12 disease but also affect the generation of ribosomes. The findings support reevaluating how to treat these patients in the future and have implications for genetic counseling.

“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,” write the investigators.

“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.”

“Vitamin B12, or cobalamin, is a dietary nutrient essential for normal human development and health and is found in animal-based foods but not in vegetables. Mutations in the genes encoding the proteins responsible for the metabolic processes involving vitamin B12 result in rare human inborn errors of cobalamin metabolism,” said co-corresponding author Ross A. Poché, PhD, associate professor of molecular physiology and biophysics at Baylor.

Patients with the most common inherited vitamin B12 disease, called cblC, suffer from a multisystem disease that can include intrauterine growth restriction, hydrocephalus, severe cognitive impairment, intractable epilepsy, retinal degeneration, anemia, and congenital heart malformations. Previous work had shown that mutations in the MMACHC gene cause cblC disease.

It also was known that some patients presenting with a combination of typical and non-typical cblC characteristics do not have mutations in the MMACHC gene, but rather in genes that code for proteins called RONIN (also known as THAP11) and HCFC1. The resulting changes in these proteins lead to reduced MMACHC gene expression and a more complex cblC-like disease.

In this study, Poché and his colleagues looked for other genes that also might be affected by HCFC1 and RONIN gene mutations.

“We developed mouse models carrying the exact same mutations that the patients with cblC-like disease have in HCFC1 or RONIN genes, and recorded the animals’ characteristics,” Poché said. “We confirmed that they presented with the cobalamin syndrome as expected, but in addition we found that they had ribosome defects. This is the first time that the HCFC1 and RONIN genes have been identified as regulators of ribosome biogenesis during development.”

The researchers demonstrate that this cblC-like disease affecting the function of RONIN and HCFC1 proteins is a hybrid syndrome as it is both a cobalamin disorder and a disease of ribosomes, or a ribosomopathy.

The findings have potential therapeutic implications. “Some cblC-like patients may respond to some extent to cobalamin supplementation, but we anticipate that will not help the issues due to ribosome defects,” according to Poché, member of the Dan L Duncan Comprehensive Cancer Center.

One step toward designing effective ribosomopathy therapies is to better understand what the defects in the ribosomes are. “We plan to functionally characterize the altered ribosomes at the molecular level to identify how their function is disrupted,” he added.

“There are many exciting aspects of this study, from the clinical implications to the basic science. The beauty is in how the work in patients is symbiotic with the work in the mouse model and how each system informs the other,” said co-author David S. Rosenblatt, MDCM, professor in the departments of human genetics, medicine, pediatrics, and biology at McGill University and senior scientist at the Research Institute of the McGill University Health Center.

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