Science & Technology

How gene mutations affect vitamin B12 deficiency

In recent years, vitamin supplements have become all the rage, with an increasing number of supplements claiming to clear your skin, promote hair growth, and even increase your IQ. Unrealistic advertisements aside, vitamins are in fact quite important. Our bodies need vitamins in small amounts to be able to grow and function properly. 

Vitamin B12, also known as cobalamin, is important for maintaining the body’s metabolism, forming red blood cells, and ensuring the proper functioning of the brain. Because the human body cannot make vitamin B12 on its own, we depend on foods, mainly animal products, to get this particular nutrient. Certain non-animal products, such as nutritional yeast and soy milk, have been fortified with vitamin B12. However, people who follow a plant-based diet are recommended to take vitamin B12 supplements to prevent cobalamin deficiency, which is characterized by feelings of weakness, tingling, smooth tongue, anemia, and sometimes memory loss. 

While such a deficiency can be reversed by vitamin B12 supplements, there are individuals for whom cobalamin supplementation is insufficient. These individuals have mutations in the genes that code for the proteins that help the body absorb or transport vitamin B12. There are currently 12 gene mutations that can lead to these inborn vitamin B12 diseases. However, the role of these genes is not well defined and thus are being studied by many researchers—one of whom is Dr. David Rosenblatt, a senior scientist in the Child Health and Human Development program at the MUHC Research Institute who has been treating patients with vitamin B12 deficiencies for over three decades. 

Rosenblatt and researchers from the Baylor College of Medicine recently published a study in Nature Communications that found that the most common type of vitamin B12 deficiency disease, clbC, is caused by a mutation in the gene Mmachc. clbC is a multisystem disease that appears in utero and can lead to growth restriction and intractable epilepsy. The Mmachc gene codes for a protein that binds cobalamin when it enters the cell. However, mutations in two other genes, Ronin and Hcfc1, also cause clbC-like disease, but with more severe symptoms. 

“The common clbC has more than 1,000 patients described from around the world,” Rosenblatt wrote in an email to The McGill Tribune. “For the rare forms that are modeled in this paper, there is only one Ronin patient and less than 20 Hcfc1 patients.”

The goal of the paper was to characterize the cobalamin disorders these gene mutations cause in greater detail by studying the function of Ronin and Hcfc1. To do this, the researchers studied the disease in a mouse model afflicted by the same gene mutations. The mice showed symptoms that are typically associated with vitamin B12 deficiency, including brain abnormalities and cardiac defects. However, the researchers also saw symptoms that were atypical of vitamin deficiency, such as craniofacial dysmorphia, or abnormal growth of the brain and facial features. This sign is typically seen in patients that have ribosomopathies—disorders where the ribosomes, the tiny machines of the cell that make proteins, are non-functional. 

To verify whether the craniofacial dysmorphia observed in the mice was a result of ribosomopathies, the authors examined protein expression in the mice. They observed that in the mice with both mutations, there was a decrease in the number of ribosomes, indicating ribosomopathy. These results show that the vitamin B12 deficiencies are much more complex than previously thought. 

“I think that there is still a great deal more that needs to be learned about the basic mechanisms in these diseases,” Rosenblatt wrote. “Knowing more about mechanisms can sometimes lead to targets for therapy.” 

Though it is too early to search for a cure, such studies are nevertheless a vital stepping stone toward understanding vitamin B12 deficiency diseases. 

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