If you sneak up on a person and say "Boo!" your average victim mayjump slightly, or utter a muted shriek, and laugh off the scare.But when a sufferer from familial startle syndrome is surprised by asudden noise or unexpected touch, he or she turns stiff as a board andfalls over, unprotected from fractures and lacerations.Also known as hereditary hyperekplexia (HEK), this is an exceedinglyrare autosomal dominant disease. Infants with HEK often die ofasphyxiation brought on by the paroxysmal muscle hypertonia that isone hallmark of the disorder. The other is a lifelong startle reactionexaggerated 10- to 20-fold above normal. (A light tap on the tip of thenose of an HEK patient will trigger the whole-body muscle-contractingspasm.)The anticonvulsant, benzodiazepine, is of some benefit in controllingHEK, but to discover better drugs, researchers need an animal modelthat mimics the human familial startle disease. Two mutant mousestrains, spasmodic and spastic, have applied for the job.Their resumes appear back-to-back in the June issue of NatureGenetics. One paper, from the University of Texas at San Antonio,bears the title, "A mis-sense mutation on the gene encoding the alpha-1subunit of the inhibitory glycine receptor in the spasmodic mouse."The other, from Duke University, is headed, "Glycine receptor beta-subunit gene mutation in spastic mouse associated with LINE-1element insertion."How do these murine candidate models qualify as molecular mimics ofthe mutated human gene that encodes the defective glycine receptor?Recent research reports that this aberrant DNA sequence resides on thelong arm of human chromosome 5. The receptor protein's alpha-1subunit allegedly disrupts the functioning of central nervous systemcells that normally react to the primordial alerts of sudden acoustic ortactile stimuli.Strychnine, once a favored poison in crime novels, serendipitouslystarted the search for HEK's biochemical nature. Peter F. Kingsmore,lead author of the Duke University paper, told BioWorld Today thestory:Two decades ago, scientists noticed that the spastic mouse strainbehaved like mice that had ingested sublethal doses of strychnine. Theyknew that this toxic plant alkaloid binds specifically to the receptor ofglycine, an amino acid active in certain neurons.At the time, Kingsmore recalled, "Nobody knew the molecular basis ofthis phenomenon. My spastic-mouse paper, and the spasmodic one byStephen G. Ryan in San Antonio both show that particular defects inthe glycine receptor gene are affected in these mutations."Specifically, a defect in the receptor's alpha-1 subunit causes Ryan'sspasmodic mice, and HEK humans. The receptor's beta subunitaccounts for Kingsmore's spastic animals.Using isotope-labeled strychnine as a marker, Ryan found a defect inthe poison's binding site in the spinal cords of animals with the startlesyndrome.There is more riding on full elucidation of these mutant genes than therare but devastating human hereditary startle syndrome. A similardisorder strikes cattle, Kingsmore said, with fully 1 percent ofAustralian herds affected. "This causes severe economic loss," heobserved. "As the disease locus hasn't been mapped in cows yet, theyhave no test, so can't eradicate the disorder. Thus, a percentage of theirherds get lost."He hopes his beta-subunit gene "could be involved in theseeconomically or clinically important diseases, in addition to the alpha-1subunit."Autosomal dominant HEK is mercifully thin on the ground. Kingsmoresuggests that "only 50 to 100 affected individuals have been reported."He added, "When you get an individual, you can get a family, as everychild of an affected person will be affected."Human geneticist Peter O'Connell, senior author of Ryan's paper, toldBioWorld Today that HEK's incidence "is probably on the order of onein 20,000." His group has identified six affected families in the U.S.,and he surmises there may be another half dozen out there.O'Connell is focusing on the strychnine-binding component of theglycine receptor's alpha subunit, "because of the pharmacologyconnecting to genetic localization of that receptor, and its localizationby linkage analysis to the families."

-- David N. Leff Science Editor

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