Researchers unravel the complexity of vitamin B12 diseases

Researchers have uncovered the genetic intricacy of two uncommon hereditary vitamin B12 disorders, classifying them as hybrid syndromes that affect both the ribosomes, the cell’s machinery for making proteins, and the vitamin B12 itself.

The scientists, using mouse models, discovered that the genes responsible for the more complicated versions of the problem not only cause the expected usual vitamin B12 sickness but also have an impact on how ribosomes, the cell’s machinery for making proteins, are produced. The results, which were reported in the journal Nature Communications, suggest rethinking future patient care strategies and have implications for genetic counselling.

“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 Dr. Ross A. Poche, 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 (the build-up of fluid in the cavities deep within the brain), 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 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, Poche 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,” Poche 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,” said Poche, 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,” Poche said.

“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 Dr. David S.