Nature Genetics pp 21 - 22 and pp 22 - 25

Charcot-Marie-Tooth (CMT) disease is one of the most common genetic disorders, affecting 1 in every 2,200 people. CMT type 4A is a severe form, involving age of onset by 1 year of age and severe weakness and atrophy of the hands and feet--the nerves are compromised in their ability to relay signals between muscle and brain.

Analysis of affected tissues indicates that there are two types of CMT type 4A. These would seem to be caused by defects in different types of cell: the Schwann cell and the nerve cell itself. The Schwann cell is analogous to the plastic coating on the wire of a lamp; it ensheathes the long fiber of the nerve cell, insulating it and thereby assisting the transduction of an electrical impulse from one end to the other. Do the different forms of the disease arise from mutations in different genes?

The answer is no, according to two studies appearing in January's issue of Nature Genetics. Jeffery Vance and colleagues from Duke University studied individuals with CMT type 4A with a loss of insulating sheath around their nerve cells. They found that each of the affected individuals has a mutation in a gene called GDAP1. In a second study, Francesc Palau and colleagues from the Instituto de Biomedicina (in Valencia, Spain) studied individuals with a loss of axon fibers in their extremities. They too found that affected individuals have mutations in the GDAP1 gene. Palau and colleagues speculate that the GDAP1 protein may influence the interaction between the nerve cell and its surrounding sheath--additional research should determine whether this is the case. In the meantime, the discoveries will aid genetic testing and counseling.

Nature Genetics pp 66 - 72 and pp 6 - 7

Geneticists study the mouse because it is comparatively easy to manipulate its genome, and thereby obtain a better understanding of gene function. But until now, the only way to create a mouse embryo with genetically different cells has been to engraft them with cells from a separate donor embryo, creating a so-called chimeric animal.

In January's issue of Nature Genetics, Neal Copeland and colleagues at The National Cancer Institute describe a method to engineer a mouse with cells that are genetically different from each other but are derived from the same embryonic stem cell. They exploit an event that is central to genetics: recombination between chromosomes. Normally, recombination occurs during a process known as meiosis, which gives rise to the so-called germ cells: sperm and eggs. Occasionally, however, it occurs during cell division and--if accompanied by segregation of the recombined chromosomes into different progeny cells--generates two cells with different genomic complements.

Copeland and colleagues have succeeded in engineering mouse embryonic stem cells that undergo mitotic recombination at defined parts of specific chromosomes, and observe that some parts of mouse chromosomes are better at recombination than other parts. Application of this technique will permit researchers to manipulate the expression of genes or collections of genes, and to trace a cell lineage during the development of the mouse embryo to an adult.

Nature Genetics pp 41 - 47

Children with leukemia face a shortened life and the discomfort of repeated chemotherapy treatment. A subset has leukemias, the chromosomes of which have a translocation--a piece of chromosome 11 has broken off and attached itself to another chromosome. These children have a particularly poor prognosis and often suffer from early relapse after chemotherapy. According to new research to be published by Nature Genetics, leukemias with the chromosome-11 translocation constitute a distinct form of leukemia.

At the moment, leukemia with the chromosome-11 translocation is classified as acute lymphoblastic leukemia, but patients do not respond well to standard therapies. By examining the expression levels of all known human genes in these leukemias, Stanley Korsmeyer and colleagues at the Dana-Farber Cancer Institute show that those with the translocation have gene expression profiles distinct from those of other leukemias. The authors conclude that these profiles distinguish the new disease, now called mixed-lineage leukemia, from two other types of leukemia--acute lymphoblastic and acute myeloid. In fact, the expression profiles of the three types of leukemia tested are so different, they can be distinguished from one another by gene expression profile alone. The expression profile of the mixed-lineage leukemia also indicates tantalizing drug targets.