Modeling Glue

Courtesy Rachel Haridsty Mouse Genome Centre, Medical Research Council, Harwell, UK MUTT AND JEFF: The Jeff mutant (bottom left), derived from an ethylnitrosourea screen for deaf mutants, has craniofacial abnormalities such as a shortened face when compared with a wild-type mouse (top left). The Jeff mutation maps to mouse chromosome 17 in a region of the mouse genome homolous to human chromosome 2p16-23. A large-scale mouse-mutagenesis program in Harwell, UK, recently turned up two new models for the most common form of childhood deafness. Otitis media (OM), as the name implies, is an inflammation of the middle ear. Although believed to be triggered by infection, studies of twins indicate a complex genetic predisposition.1 Children who have malformed eustachian tubes--those with cleft palate or Down syndrome, for instance--seem to be particularly vulnerable. When OM is accompanied by the buildup of fluid, it is called OM with effusion, or "glue ear," and most children will experience at least one episode of this in their lives. The condition presents as partial deafness, and affected children cannot hear human speech, which can result in impaired social development. Surgery, which is recommended for the worst cases, involves drilling a tiny hole in the eardrum to allow the fluid to escape. As with all surgeries, however, the procedure carries risks. Researchers are trying to develop a new therapy for the most susceptible children. JEFF AND JUNBO Steve Brown, of the Medical Research Council's Mammalian Genetics Unit and the Mouse Genome Centre in Harwell, and colleagues found the Jeff and Junbo genes after studying more than 30,000 mutant mouse lines that were generated with the powerful chemical mutagen ethylnitrosourea. Jeff is a promising model because there are no indications of the sensorineural form of deafness that commonly accompanies aging.2 The mice have pus-filled middle ear cavities, elevated hearing thresholds, and mild craniofacial abnormalities. "They look very much like children who have got a chronic inflammatory middle-ear condition," says Brown. Glenis Scadding, a consultant physician in allergy and rhinology at the Royal National Throat, Nose, and Ear Hospital in London, agrees. She is intrigued by the craniofacial abnormalities of the Jeff mice, because, she says, "Children who have [glue ear] problems tend to have a slightly altered skull shape." But, she adds, head shape is probably not the only factor that predisposes a child to the condition. Genetic factors also may be controlling immunity and resistance to the allergens involved. Jeff and Junbo turned up after a battery of tests, what Brown refers to as his "mouse clinic," were done to highlight any interesting disease models. The researchers noticed the mice because they failed to jump in response to an acoustic startle test. The responsible genes were mapped to chromosome 17 for Jeff and chromosome 3 for Junbo. The Junbo research could be published later this year, Brown says. Similar mutagenesis and screening techniques are used at the Jackson Laboratory in Bar Harbor, Maine, says team leader Wayne Frankel. Their work recently turned up a potential model for epilepsy.3 "We got peripherally interested in hearing because one of our seizure mutants, Stargazer, has a mild vestibular deficit," says Frankel. Because the acoustic startle test is one of those they use in their own mouse clinic, Frankel and coworkers also have stumbled across a number of hearing-impaired mice with middle ear defects. Lab member Qing Yin Zheng is developing a screening program specifically for OM. Brown has cloned the Jeff and Junbo genes and says he will begin screening human populations affected by OM for similar mutations. Jeff and Junbo are just the start, he says. "We can expect a continuing expansion of the mouse mutant resource and an increasing number of models for the study of human genetic disease." Laura Spinney (LFSpinney@compuserve.com) is a freelance writer in London. References 1. M. Rovers et al., "Heritability of symptom domains in otitis media: A longitudinal study of 1,373 twin pairs," Am J Epidemiol, 155:958-64, 2002. 2. R.E. Hardisty et al., "The deaf mouse mutant Jeff (Jf) is a single gene model of otitis media," J Assoc Res Otolaryngol, in press. 3. Y. Yang et al., "Spontaneous deletion of epilepsy gene orthologs in a mutant mouse with a low electroconvulsive threshold," Hum Mol Genet, 12:975-84, May 1, 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

Modeling Glue

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