Most people are infected with the Epstein-Barr virus (EBV) at an early age, and generally only suffer symptoms akin to having a 'cold'. After early childhood, however, EBV infection can result in infectious mononucleosis. In a few rare cases, EBV infection in infant boys unleashes a massive immune response, leading to X-linked lymphoproliferative disease (XLP), of which very few patients survive. David Bentley, of The Sanger Centre, and colleagues have now discovered that patients (usually male) susceptible to XLP have a mutation in the SH2D1A gene. A similar discovery is reported by Cox Terhorst, of Harvard Medical School, and colleagues, in Nature (1 October 1998), where it is also revealed that the protein encoded by SH2D1A -- called SAP -- plays a critical role in communicating signals between cells of the immune system. Together, these findings provide insight into how cells of the immune system interact to instigate a coordinated attack on viral infections.
EBV first infects the throat but shortly afterwards invades the B cells (the antibody-producing cells of the immune system), triggering them to rapidly multiply. T cells recognize the EBV-infected B cells as foreign and instigate a massive inflammatory response, with the recruitment of other cells of the immune system in the fight against the virus. The signals between B cells and T cells are communicated via the SLAM protein, a receptor on the surface of both cell types. SAP, which is encoded by SH2D1A, binds the SLAM receptor and regulates communication between T and B cells. In an accompanying News & Views article, Michel Sadelain, of the Memorial Sloane-Kettering Cancer Center, and Elliott Kieff, of Harvard Medical School, discuss how mutations of SH2D1A cause unregulated signalling between T cells and B cells, leading to excessive proliferation and an inappropriate immune response to EBV infection, with devastating consequences.
Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding genepp 129 - 135 Alison J. Coffey, Robert A. Brooksbank, Oliver Brandau, Toshitaka Oohashi, Gareth R. Howell, Jacqueline M. Bye, Anthony P. Cahn, Jillian Durham, Paul Heath, Paul Wray, Rebecca Pavitt, Jane Wilkinson, Margaret Leversha, Elizabeth Huckle, Charles J. Shaw-Smith, Andrew Dunham, Susan Rhodes, Volker Schuster, Giovanni Porta, Luo Yin, Paola Serafini, Bakary Sylla, Massimo Zollo, Brunella Franco, Alessandra Bolino, Marco Seri, Arpad Lanyi, Jack R. Davis, David Webster, Ann Harris, Gilbert Lenoir, Genevieve de St Basile, Alison Jones, Bernd H. Behloradsky, Helene Achatz, Jan Murken, Reinhard Fassler, Janos Sumegi, Giovanni Romeo, Mark Vaudin, Mark T. Ross, Alfons Meindl & David R. Bentley doi:10.1038/2424 Abstract|Full
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Why commonplace encounters turn to fatal attractionpp 103 - 104 Michel Sadelain & Elliott Kieff doi:10.1038/2569 Abstract|Full
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Mother knows best -- but paternal genes have a say
Nature Genetics pp 163 - 169 and pp 108 - 109
A common trait of many mammals is the instinctual nurturing of newborns by their mothers. In recent years, scientists have discovered a number of genes that appear to guide this caring behaviour. Now a study by Azim Surani, of Cambridge University, and colleagues has identified a mouse gene that makes for good motherhood. The researchers found that when the Mest gene is defective in females who give birth, the new mothers no longer follow nature's rules. Mest-deficient mothers neglect their young after birth: they fail to clean them, are not good nest builders and are slow to fetch pups back to the nest when they stray -- indeed, most of the pups perish as a result of maternal neglect. Normally, Mest is found in the nervous system of adult mice, indicating that it is likely to influence the neural hardware that governs maternal responses.
Surani and colleagues have shown that the pattern of Mest expression is an example of a phenomenon known as gene imprinting. Genes usually exist in two copies, one inherited from mother and one from father -- but, in the case of imprinted genes, only one of the two copies is active; the other is 'mute'. Only the paternal copy of Mest is active. The finding that female mice lacking Mest are bad mothers is the first demonstration that paternal genes influence maternal behaviour. In an accompanying News & Views article, Robert Bridges, of Tufts University School of Veterinary Medicine, emphasizes that the complexity of maternal behaviour is not controlled by a single gene.
Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mestpp 163 - 169 Louis Lefebvre, Stéphane Viville, Sheila C. Barton, Fumitoshi Ishino, Eric B. Keverne & M. Azim Surani doi:10.1038/2464 Abstract|Full
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The genetics of motherhoodpp 108 - 109 Robert S Bridges doi:10.1038/2399 Abstract|Full
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X marks the spot for prostate cancer susceptibility
Nature Genetics pp 175 - 179
Prostate cancer causes more than 35% of all cancer cases affecting men. While genetic susceptibility to the cancer has been suspected, attempts to identify the genes involved have been hampered by a large number of patients, a wide spectrum of clinical features, and the likelihood that many different factors contribute to susceptibility. Now, through the massive collaborative efforts of five international research groups, in the United States, Sweden and Finland, a gene conferring susceptibility to prostate cancer has been pinpointed to a narrow region on the X chromosome. This gene is predicted to be responsible for approximately 16% of all hereditary prostate cancer cases.
The researchers used a powerful genetic strategy: comparisons were made between members of prostate cancer families and normal people to identify parts of the genomic landscape that are shared in affected individuals -- providing 'signposts' to where the culprit gene lies. While this is the second major susceptibility gene for prostate cancer that has been localized using this approach (the other lies on chromosome 1), researchers are confident that this gene will be easier to isolate than the one on chromosome 1 because much more is known about the sequence and arrangement of genes on the X chromosome, and because it is easier to follow the inheritance of a gene on a sex chromosome.
Evidence for a prostate cancer susceptibility locus on the X chromosomepp 175 - 179 authors Published online: Abstract|Full
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A cell's survival depends on the ability to divide properly -- this involves the duplication of each chromosome, with each copy moving to opposite sides of the cell before the mother cell splits into two daughter cells. The chromosomes are pulled to each side by microtubules and the action of the microtubules is coordinated by organizing centres called centrosomes which lie at opposite poles of the mother cell during division. Subrata Sen, of University of Texas M.D. Anderson Cancer Center, and colleagues now reveal a role for the protein STK15 in centrosome function, and how abnormally high levels of this protein may lead to cancer.
STK15 is normally found in the complex of proteins that make up the centrosome. It is more abundant in tumour cells and the gene encoding it is often found amplified to multiple copies in breast and colon cancers, suggesting that it may be involved in the formation or development of cancers. Sen and colleagues demonstrate that higher levels of STK15 result in the formation of extra centrosomes in the cell and this, in turn, leads to chromosomes being split unevenly during division. This loss or gain of chromosomes makes cells susceptible to becoming cancerous.
In an accompanying News & Views article, Stephen Doxsey, of the University of Massachusetts Medical Center, discusses the role of centrosomes as central players in cancer progression and why STK15 is likely to be one of many participants in the pathway that controls centrosome function.
Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformationpp 189 - 193 Hongyi Zhou, Jian Kuang, Ling Zhong, Wen-lin Kuo, Joe Gray, Aysegul Sahin, Bill Brinkley & Subrata Sen doi:10.1038/2496 Abstract|Full
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The centrosome—a tiny organelle with big potentialpp 104 - 106 Stephen Doxsey doi:10.1038/2392 Abstract|Full
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Lafora disease (LD) is a severe form of epilepsy which is characterized by seizures and progressive neurological degeneration, eventually resulting in death within 10 years after the appearance of the first symptoms. People with LD accumulate aggregates of unprocessed glycogen, called Lafora bodies, in the brain; this is believed to cause neuronal death. Steve Scherer, of The Hospital for Sick Children, and colleagues have discovered that this devastating condition is caused by mutations in a newly discovered gene, EPM2A. Its protein product appears to be a signalling molecule which may mediate glycogen metabolism. These findings not only reveal a new cause of epilepsy (most other epilepsy genes encode ion channel proteins) -- they also point to a new metabolic pathway of the brain.
Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsypp 171 - 174 Berge A. Minassian, Jeffrey R. Lee, Jo-Anne Herbrick, Jack Huizenga, Sylvia Soder, Andrew J. Mungall, Ian Dunham, Rebecca Gardner, Chung-yan G. Fong, Stirling Carpenter, Laura Jardim, P. Satishchandra, Eva Andermann, O. Carter Snead III, Iscia Lopes-Cendes, Lap-Chee Tsui, Antonio V. Delgado-Escueta, Guy A. Rouleau & Stephen W. Scherer doi:10.1038/2470 Abstract|Full
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Cells are faced with difficult decisions during development and one of the first and most crucial is whether to become a nerve or another cell type. Cells of an embryo are programmed to become nerves (or neurons) by default, and previous studies have suggested that cells fated not to become neurons are instructed by Rest, a 'master regulator', which turns off specific genes that would normally specify a neural destiny. David Anderson, of the California Institute of Technology, and colleagues have now rendered the theory that Rest serves as master regulator defunct. They demonstrate that non-neural cells in mouse and chicken embryos devoid of Rest express neural-specific genes, but do not become neurons, suggesting multiple factors are required to suppress the default neural state. As discussed by Ali Hemmati-Brivanlou, of Rockefeller University, in an accompanying News & Views article, these findings highlight the complexity of neural development and indicate that there are likely to be a series of integrated molecular steps that instruct neural differentiation.
NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesispp 136 - 142 Zhou-Feng Chen, Alice J. Paquette & David J. Anderson doi:10.1038/2431 Abstract|Full
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Should the master regulator Rest in peace?pp 109 - 110 Ali Hemmati Brivanlou doi:10.1038/2402 Abstract|Full
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Despite the complexity of factors regulating body fat, scientists have made dramatic inroads into understanding the genes that predispose to obesity. Researchers have now uncovered another genetic component controlling appetite and energy expenditure with the discovery that mutations in the MC4R gene cause obesity. Two groups, one led by Stephen O'Rahilly, of Addenbrooke's Hospital, and another by Philippe Froguel, of Institut Pasteur de Lille, have independently discovered that the gene which encodes the melanocortin-4 receptor is mutated in some families with a history of obesity.
The melanocortin-4 receptor is found in the brain and binds the -melanocyte-stimulating hormone (MSH) -- this interaction turns off the impulse to eat. The nerves that manufacture -MSH are stimulated by leptin, a hormone encoded by a gene mutated in some cases of obesity. This recent discovery reveals that the MC4R and leptin genes act in a common pathway controlling food intake and that both predispose to obesity.
Mutation of only one copy of MC4R causes obesity -- this is unique compared with other genetic defects associated with obesity, where both copies of the gene responsible need to be mutated before physical effects are manifested. It is possible that subtle variations in MC4R may be an underlying cause of more common forms of obesity.
A frameshift mutation in MC4R associated with dominantly inherited human obesitypp 111 - 112 Giles S.H. Yeo, I. Sadaf Farooqi, Shiva Aminian, David J. Halsall, Richard G. Stanhope & Stephen O'Rahilly doi:10.1038/2404 Abstract|Full
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A frameshift mutation in human MC4R is associated with a dominant form of obesitypp 113 - 114 Christian Vaisse, Karine Clement, Bernard Guy-Grand & Philippe Froguel doi:10.1038/2407 Abstract|Full
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-melanocyte-stimulating hormone (
