“Mutations in genes encoding proteins responsible for vitamin B12-related metabolism lead to rare inborn errors in humans in cobalamin metabolism,” said co-author Dr. Ross A. Poch, an associate professor of molecular physiology and biophysics at Baylor.
The patient with the most common inherited vitamin B12 disease, termed cblC, had a multisystem disease that included intrauterine growth restriction, hydrocephalus, severe cognitive impairment, intractable epilepsy, and macular degeneration. conjunctivitis, anemia, and congenital heart defects.
Previous research has shown that mutations in the MMACHC gene cause cblC disease.
It is also known that some patients presenting with a combination of typical and atypical cblC features do not have mutations in the MMACHC gene but in a gene that encodes proteins known as RONIN (also known as RONIN). THAP11) and HCFC1. As a result, changes in these proteins lead to decreased MMACHC gene expression and a more complex cblC-like disease.
In this study, Poch and his colleagues looked for other genes that might also be affected by mutations in the HCFC1 and RONIN genes.
“We developed mouse models carrying the same mutations as those with cblC-like disease in the HCFC1 or RONIN genes, and recorded the animal characteristics,” says Poche.
“We confirmed that they had the expected cobalamin syndrome, but in addition, we found that they had a ribosomal defect. This is the first time that the HCFC1 and RONIN genes have been identified as regulators. ribosomes during development.”
The researchers demonstrate that the cblC-like disease affecting the function of the RONIN and HCFC1 proteins is a hybrid syndrome because it is both a cobalamin disorder and a ribosome, or ribosomal, disease.
The findings have potential therapeutic implications. Poch, a member of the Dan L Duncan Comprehensive Cancer Center, said: “Some cblC-like patients may respond to some extent to cobalamin supplementation, but we anticipate that will. does not help with problems caused by ribosomal defects.”
One step towards designing effective therapies for ribosomes is to better understand defects in ribosomes. “We intend to functionally characterize the altered ribosomes at the molecular level to determine how their function is disrupted,” says Poche.
“There are so many interesting aspects of this research, from the clinical implications to the basic science.
The beauty is how they work on patients in symbiosis with work on mouse models and how each system informs the other,” said co-author Dr. David S. Rosenblatt, professor in the department of human genetics , medicine, pediatrics, and biology at McGill University and senior scientist at the Research Institute of McGill University Medical Center.