Nature Genetics pp 223 - 231, pp 211 - 212 and pp 200 - 201

Mitochondria are small 'organelles' that reside within cells and have one of the most important roles in cellular function: they are the power generators, producing the all-important energy molecule ATP. Mitochondria contain their own DNA, from which they make some of the products necessary for ATP production, but they rely on the genes in the cell nucleus—where the vast majority are located—to supply most of the components.

So what happens when there's a mitochondrial blackout? One clinical symptom of impaired mitochondrial function is impaired function and weakness of muscles—not a surprise, as that's where energy is generally the most needed. One such syndrome, progressive external ophthalmoplegia (PEO), is characterized by lack of eye movements and exercise intolerance. Within the mitochondria of individuals afflicted with PEO, large pieces of the DNA are missing—without which the mitochondria cannot function properly.

New results from two independent groups indicate why the mitochondrial DNA deletions may be present in PEO. In a large group of individuals with PEO, Johannes Spelbrink (of Tampere University Hospital) and colleagues found one gene whose protein, Twinkle, is similar to proteins that unwind and reconfigure DNA. A second group, led by Christine Van Broeckhoven (of the Flanders Interuniversity Institute for Biotechnology), identified another factor—DNA polymerase gamma (POLG), a protein that replicates DNA—that is mutated in other individuals afflicted with PEO. Both of these types of proteins are essential for propagation of DNA, providing a very good basis for understanding why these defects could lead to PEO.

As indicated in an accompanying News & Views article by Carlos Moraes (of the University of Miami School of Medicine), "these reports confirm...that the mitochondrial DNA repair/replication machinery is involved in at least some cases of PEO" and are "a significant step towards understanding [these] disorders."

Nature Genetics pp 241 - 249 and pp 198 - 200

With a large majority of human gene sequences now to hand, one the next big challenges for geneticists is to understand which biological processes are mediated by which genes.

As mice and humans (and their genomes) are similar in many respects, and mice are more amenable to genetic toggling, one strategy is to figure out the function of mouse genes to gain clues to the function of their human counterparts. And, as is the way in the age of 'omics', doing this on a large scale, in a systematic manner is the goal.

To this end, William Skarnes (of University of California, Berkeley) and colleagues now report on a reverse genetics procedure, called gene trapping. This general procedure, which has been used for researchers for some time, involves the 'pincering' out of a gene in a mouse embryonic stem (ES) cell, from which a mouse is then engineered. Sequencing the 'pincered' sequence reveals the identity of the gene, for which the generated mouse is deficient. One limitation has been that the genes amenable to trapping have been limited to those that are expressed at moderate or large quantities in the ES cell. By tweaking the method, Skarnes and colleagues have been able to not only selectively target genes encoding secretory and cell-surface proteins, but also, genes that are expressed at lower levels in the ES cell. The 500 gene-trapped ES cells generated by Skarnes and colleagues (and available to researchers upon request) represent a substantive resource for exploring gene function. Ian Jackson (of the Medical Research Council, Edinburgh) discusses the study and its context in an accompanying News & Views article.

Nature Genetics pp 261 - 265 and pp 202 - 203

Contrary to common perception, bones are dynamic tissues in which some cells, the osteoblasts, contribute to bone deposition, and others, the osteoclasts, promote bone resorption. Toggling the balance between these opposing activities results in bone formation and remodeling during growth and regeneration. This balance would seem to be upset in people with the 'vanishing bone' syndromes—a group of disorders where the affected bones are excessively resorbed and destroyed (osteolysis). Other aspects of these diseases include erosion of the joints between the phalanxes, reminiscent of rheumatoid arthritis. Until now, the cause of vanishing bone syndromes was unknown.

John Martignetti (of Mount Sinai School of Medicine, New York) and colleagues now report the cause of one form of inherited osteolysis: mutations in the gene encoding a matrix metalloproteinase, which belongs to a large family of proteases that degrade components of the extra-cellular matrix (ECM). In bones, the ECM is thought to be essential for proper differentiation of the surrounding cell types, such as osteoblasts and osteoclasts, and may thus affect the equilibrium between bone formation and resorption. Diminished ECM, however, is thought to underlie osteolysis, and so mutations in a gene whose product breaks down the extracellular matrix comes as something of a surprise.

As discussed in an accompanying News & Views article by Thiennu Vu (of University of California, San Francisco, California), this study should inspire caution when designing therapeutic approaches to disorders caused by the disruption of the ECM.