In new gene disorder, B12 can’t get to cells

MCGILL (CAN) — Scientists have identified a key gene in the transport of vitamins to cells—and discovered a genetic disease related to vitamin B12 deficiency.

Some people have inherited conditions that leave them unable to process vitamin B12, which is essential to human health. As a result they are prone to serious health problems, including developmental delay, psychosis, stroke, and dementia.

The discovery, reported in the journal Nature Genetics, will help doctors better diagnose this rare genetic disorder and open the door to new treatments.


“We found that a second transport protein was involved in the uptake of the vitamin into the cells, thus providing evidence of another cause of hereditary vitamin B12 deficiency”, says David Rosenblatt, one of the study’s co-authors and a scientist in medical genetics and genomics at the Research Institute of the McGill University Health Centre (RI MUHC).

“It is also the first description of a new genetic disease associated with how vitamin B12 is handled by the body,” he says.

These results build on previous research by the same team with their colleagues in Switzerland, Germany, and the US. In previous work, the researchers discovered that vitamin B12 enters our cells with help from a specific transport protein. In this study, they were working independently with two patients showing symptoms of the cblF gene defect of vitamin B12 metabolism but without an actual defect in this gene.

Their work led to the discovery of a new gene, ABCD4, associated with the transport of B12 and responsible for a new disease called cblJ combined homocystinuria and methylmalonic aciduria (cblJ-Hcy-MMA).

Using next generation sequencing of the patients’ genetic information, the scientists identified two mutations in the same ABCD4 gene in both patients. “We were also able to compensate for the genetic mutation by adding an intact ABCD4 protein to the patients’ cells, thus allowing the vitamin to be properly integrated into the cells,” explains Matthias Baumgartner, senior author of the study and a professor of metabolic diseases at Zurich’s University Children’s Hospital.

Vitamin B12, or cobalamin, is essential for healthy functioning of the human nervous system and red blood cell synthesis. Unable to produce the vitamin itself, the human body has to obtain it from animal-based foods such as milk products, eggs, red meat, chicken, fish, and shellfish—or vitamin supplements. Vitamin B12 is not found in vegetables.

“This discovery will lead to the early diagnosis of this serious genetic disorder and has given us new paths to explore treatment options. It also helps explain how vitamin B12 functions in the body, even for those without the disorder,” says Rosenblatt, the director of one of only two referral laboratories in the world for patients suspected of having this genetic inability to absorb vitamin B12.

This work was funded by the Canadian Institutes of Health Research (CIHR), the Swiss National Science Foundation, and the Deutsche Forschungsgemeinschaft.

Study co-authors contributed from University Children’s Hospitals in Basel and Zürich, Switzerland; McGill and RI MUHC; Genome Quebec Innovation Centre; University Children’s Hospital in Münster, Germany; University of Cologne in Germany; University of Utah; ARUP Laboratories in Salt Lake City, Utah; Leibniz Institute for Arteriosclerosis Research in Münich, Germany; Charité University Medicine in Berlin, Germany; and University Children’s Hospital in Mainz, Germany.

Source: McGill University