Scientists may have finally cracked a long-standing mystery about a rare genetic disorder--the inability to break down vitamin B-12--that can lead to three devastating conditions. A new study has linked them to mutations in different places on the same gene. At the same time, the finding could help solve the puzzle of how healthy people process the essential nutrient.
Vitamin B-12 plays a critical role in nerve function, the production of red blood cells and DNA, and other vital processes. So it's not surprising that people lacking a key protein for breaking down the vitamin so the cells can use it develop devastating health problems, including difficulty learning, psychosis, and anemia. But even though the same protein is affected in all patients, some develop a condition called homocystinuria, some develop another called methylmalonic aciduria, and still others develop both. Seeking to solve this riddle, a team led by geneticist Brian Fowler of University Children's Hospital in Basel, Switzerland, went searching for the cause of the disorder in cells obtained from seven patients.
Through a series of experiments, the researchers pinpointed what appeared to be the responsible gene, dubbed MMADHC. Compared to healthy people, people with any of the three conditions had mutations in MMADHC; in lab tests, normal copies of the gene delivered into the patients' cells restored those cells' ability to process vitamin B-12, the researchers report in the 3 April issue of the New England Journal of Medicine.
But the location of the mutations may explain the variety of the three conditions. Patients with methylmalonic aciduria had mutations on one end of the gene, which the team speculates would result in a semifunctional protein that leads to partial breakdown of vitamin B-12 and the buildup of byproducts that cause the disorder. Likewise, patients with homocystinuria had mutations on the opposite end of the gene, that would allow for partially processing another component of vitamin B-12, resulting in different byproducts likely to cause this condition, the researchers say. Patients with both conditions simultaneously had mutations near the middle of the gene that would cause an entirely dysfunctional protein--and trigger both disorders. David Rosenblatt, a geneticist at McGill University in Montreal, Canada, and co-author of the study, says that the scenario still needs to be confirmed.
The findings may lead the way to treatments, such as gene therapy, says Ralph Green, a hematologist at the University of California, Davis. Charles Venditti, a biochemical geneticist at the National Human Genome Research Institute in Bethesda, Maryland, says now that researchers know where to look, screenings of newborns may detect people with milder forms of the vitamin B-12 disorder who have up until now gone unrecognized; they could have fewer mutations or mutations that allow for a better-functioning protein.
The finding may also help scientists understand how cells of healthy people transport vitamin B-12 into the mitochondria, a process that until now has stumped them. The sequence of the MMADHC gene is similar--but not identical--to that of a transporter gene certain bacteria use for shuttling the vitamin around, so Rosenblatt speculates that the protein produced by the gene may be a novel transport system that human cells use to move vitamin B-12 into their mitochondria. That too, needs to be verified in experiments, Venditti and Green say.