Vitamin B12 deficiency: tracing the causes

They have discovered an important gene that determines how vitamin B12 gets into cells. Their discovery enables the diagnosis and treatment of this rare genetic disease.

Vitamin B12 is vital for cell division, the synthesis of red blood cells and the functioning of the nervous system. Unable to produce the vitamin itself, the human body has to obtain it via animal proteins. So far it has been known that on its way into the cell vitamin B12 is absorbed by little organelles, so-called lysosomes.

From there, the vitamin enters the cell interior with the aid of the transport protein CblF, which was discovered by the same research team three years ago. The researchers now show that a second transport protein is actually necessary for this step, thus providing evidence of another cause of hereditary vitamin B12 deficiency.

Gene mutation prevents transport of vitamin B12
The scientists in Switzerland and Canada each examined an individual patient with symptoms of the CblF gene defect, yet without an actual defect in this gene. Using different methods, including sequencing all the coding segments of the genetic information, they were able to identify two mutations in the same gene in both patients.

The gene in question encodes the protein ABCD4, which was previously known as an ABC transporter in other cell organelles, albeit with an insufficiently defined function. It is now clear that it is a vitamin B12 transporter: “We were able to detect ABCD4 in the lysosomes of human skin cells – right next to the already known CblF protein” explains Matthias Baumgartner, a professor of metabolic diseases at Zurich’s University Children’s Hospital. By adding intact ABCD4 protein to the patients’ cells, the researchers were able to rescue the vitamin B12 transport and compensate for the genetic defect. “We also discovered that a targeted change in the ATP binding site of ABCD4 triggered a loss of function,” says Baumgartner. Thus both ABCD4 and CblF proteins are responsible for the transfer of vitamin B12 from the lysosomes into the cell interior, and ATPase activity is involved. Baumgartner concludes: “The results obtained enable the diagnosis and treatment of this hereditary vitamin B12 deficiency.”

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

Further reading:
David Coelho, Jaeseung C. Kim, Isabelle R. Miousse, Stephen Fung, Marcel du Moulin, Insa Buers, Terttu Suormala, Patricie Burda, Michele Frapolli, Martin Stucki, Peter Nürnberg, Holger Thiele, Horst Robenek, Wolfgang Höhne, Nicola Longo, Marzia Pasquali, Eugen Mengel, David Watkins, Eric A. Shoubridge, Jacek Majewski, David S. Rosenblatt, Brian Fowler, Frank Rutsch, Matthias R. Baumgartner. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nature Genetics. 26 August, 2012. Doi: 10.1038/ng.2386
Contact:
Prof. Dr. med. Matthias Baumgartner
Department of Metabolic Diseases
University Children’s Hospital Zurich
Phone +41 44 266 77 22
Email: matthias.baumgartner@kispi.uzh.ch