Researchers at Baylor College of Medicine and collaborating institutions have unravelled the mysteries surrounding two rare inherited vitamin B12 diseases that affect the same gene but are clinically distinct from the most common genetic vitamin B12 disorder.
The study shows 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. The study was carried out on mice wherein researchers 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 protein-building machinery of the cell.
The findings, published in the journal Nature Communications, support reevaluating how to treat these patients in the future and have implications for genetic counseling.
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, researchers looked for other genes that also might be affected by HCFC1 and RONIN gene mutations. They 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.