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Afrikaner clues to schizophrenia. Founder populations, which originate from relatively few individuals and tend to remain isolated over many generations, offer scientists unique opportunities to study the genetics of disease. Two recent studies led by Maria Karayiorgou report on the Afrikaner population, descendants of South African settlers originally from The Netherlands and other parts of northern Europe. Karayiorgou’s first study, on 260 Afrikaners with schizophrenia, reports on the genealogy of this population and evaluates the potential it has to yield clues about genes that are linked to the disease. When Karayiorgou compared the clinical data on the Afrikaner patients with data from a sample of American patients with schizophrenia, she found many similarities. “The comparison suggests that our genetic findings in the Afrikaner study will be applicable to other populations and schizophrenia in general,” she says. In the second report, Karayiorgou and her colleagues performed a genome-wide scan on multiple members of 143 of the families, and found specific locations on chromosomes 1, 9 and 13 that may have links to schizophrenia — including a locus on chromosome 1 that had not previously been identified. Furthermore, the researchers identified one patient carrying a uniparental disomy of his entire chromosome 1, a finding that may prove extremely valuable in their efforts to isolate the culprit gene from chromosome 1.
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), January 2004, and American Journal of Human Genetics, March 2004.

A new tool for membrane channel studies. A toxin derived from the polyps of soft-bodied marine animals called zoanthids could help scientists understand how sodium and potassium ions are pumped — that is, moved against their natural tendencies — across the membranes of all animal cells. But before this toxin, called palytoxin, can be scientifically exploited, researchers need to know more about how it works. David Gadsby, head of the Laboratory of Cardiac and Membrane Physiology, and postdoc Pablo Artigas, have now conducted extensive studies of how palytoxin interacts with sodium/potassium pumps in human kidney cells and guinea pig muscle cells. Their results indicate that the pump’s affinity for palytoxin varied over several orders of magnitude depending on the ratio of the potassium and sodium ions on either side of the membrane and on the metabolic state of the cell. The researchers also showed that the narrowest part of the palytoxin-induced ion pathway through the pump is about 0.75 nanometers wide and that prior or simultaneous exposure to a cardiotonic steroid weakens palytoxin’s ability to bind to it. Gadsby and Artigas say their research will help them, and other scientists who want to use palytoxin, to examine the structure of gates in the pump that regulate the uphill passage of sodium and potassium ions through practically all cell membranes.
Journal of General Physiology, March 2004.

Characterizing kinases. In the neuroscience community, there’s a tremendous amount of interest in kinase inhibitors, which block the activity of specific proteins (called kinases) believed to contribute to Alzheimer’s disease, Parkinson’s Disease and other neurodegenerative disorders. Now Laurent Meijer, a visiting professor in Paul Greengard’s Laboratory of Molecular and Cellular Neuroscience, has characterized how a class of kinase inhibitors known as indirubins — chemicals derived from indigo-producing plants, certain species of mollusks and various bacteria — bind to kinases. Meijer’s studies, which were conducted in collaboration with colleagues in France, Italy, Greece and the United Kingdom, provide scientists with additional tools to investigate the functions of two specific kinases — glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases (CDKs). The scientists also hope their research will eventually lead to new therapeutic compounds useful in treating Alzheimer’s, cancer and other diseases in which CDKs and GSK-3 are implicated.
Journal of Medicinal Chemistry, February 2004.

Turning off embryonic defects.In Elaine Fuchs’s Laboratory of Mammalian Cell Biology and Development, there’s a lot of discussion about two proteins known as Lef and Tcf, which regulate biological processes such as tissue development, stem cell maintenance and tumor formation. Three of the four Lef/Tcf genes of the mouse have been shown to function by switching on the Wnt signaling pathway. To learn more about what the remaining Tcf gene does, Brad Merrill, a postdoc in Fuchs’s lab, produced a line of mouse mutants that lack Tcf3. The mutant embryos proceeded normally in their earliest stages, but displayed defects in the process that shapes the basic architectural plan of vertebrate embryos. This was surprising, because it suggested that the normal function of Tcf3 might be to keep the Wnt pathway turned off rather than to turn it on. When Merrill and Fuchs studied the mutant embryos in more detail, they found that several genes associated with the formation of the basic body plan did not function correctly in the absence of Tcf3. As a result of these molecular defects, Tcf3 mutant mouse embryos exhibited stunning abnormalities, including multiple heads and tails. The scientists conclude that during early embryogenesis, Tcf3 acts as a repressor rather than an activator of the Wnt signaling pathway and its repressor function restricts the induction of the anterior-posterior axis in the developing embryo.
Development, January 2004.

March 26, 2004



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