Starting with this post, we inaugurate what we hope and expect will be a series of comments from authors of recently published papers in Nature Genetics (our own form of guestblogging). As we all know, the limitations of the formal primary scientific paper, in both style and format, relegates a fair amount of interesting background information about a piece of science to the sidelines. Only those who are ‘in the loop’ in a certain research area may know about the potentially instructive twists and turns of its gestation, and non-scientist readers may wonder about what motivated the work to begin with. Our colleagues at Nature have initiated an ‘Authors’ page, which provides an opportunity to take a slightly broader view of a publication and the scientists who produce it. The advantages of doing so on a blog include both extra space and the opportunities to link to relevant information.

For our first try at this, we’ve asked Dr. David Rosenblatt of McGill University to comment on his recent NG publication on the identification of the mutation underlying the most common inborn error of vitamin B12 metabolism.

Dr. Rosenblatt comments:

As a clinical scientist, I have been interested in the classification of patients with inherited disorders of vitamin metabolism for the past 35 years. My laboratory is one of two in the world that serves as an international resource for patients with inborn errors of folate and vitamin B12 metabolism. The disease discussed in our Nature Genetics publication is the cblC form of combined homocystinuria and methylmalonic aciduria. Although not by any means common, this is the most common of the inborn error of vitamin B12 metabolism and there are about 350 known patients around the world. This disease has some historical interest, because it was partly due to the pathological findings in one of these patients that the homocysteine theory of atherosclerosis was put forward.

The vast majority of patients with this disease come to medical attention in the first year of life. Their chief clinical findings tend to be developmental delay and anemia. In several unusual patients, the age of onset has been much older--either in adolescence or adulthood--and in these patients, the symptoms have been mainly neurological. It is the finding of elevations of both homocysteine and methylmalonic acid in the blood and/or urine that leads to suspicion of the diagnosis. Confirmation has required study of cultured fibroblasts. Cells from cblC patients do not incorporate labeled propionate or methyltetrahydrofolate into macromolecules and do not synthesize the vitamin B12 cofactors, methylcobalamin and adenosylcobalamin. Somatic cell complementation studies make the final diagnosis, as the defect in the cells will not be corrected by fusion with known cblC cells.

The gene product missing in cblC disease had long been thought to be a reductase that takes cobalt in cobalamin from the 3+ to the 2+ oxidation state, as a number of publications had shown abnormality of this function in cell extracts. However, targeting genes with domains suggestive of reductases did not yield results. In the end, the gene product is still of unknown function but has homology with tonB, a bacterial protein that is implicated in vitamin B12 transport.

A number of years ago, Janet Atkinson, working with Johanna Rommens, mapped the gene to chromosome 1 and reported these results at the annual meeting of the American Society of Human Genetics. Jamie Tirone, a Ph.D. student in my laboratory started a project that began, not with families, but with DNA from patients with cblC. The approach was first to start with patients from consanguineous unions, saturate the area with microstaellites and look for regions of homozygosity. Subsequently, DNA from non-consanguineous patients was studied and a combination of homozygosity mapping and haplotype analysis was employed. As described in our paper, this eventually led to discovery of the gene and interestingly of a common mutation. Unfortunately, about a year into this work, Jamie Tirone died tragically; Jordan Lerner-Ellis continued the project, and ultimately identified the gene.

This work can be used immediately to help families at risk for cblC disease. It allows for early molecular diagnosis and carrier detection. It can be used for prenatal diagnosis with even the possible consideration of prenatal therapy with vitamin B12. Although not known to be effective, the latter approach has been described in a number of other inborn errors of vitamin B12 metabolism. For those who want prenatal diagnosis for reproductive counseling, mutation analysis allows for earlier diagnosis and, in theory, even pre-implantation diagnosis.