The study is described in an article published March 21 in the open-access journal PLoS Genetics.

Genetic defects in certain DNA repair factors like the CSB protein have been known for some time to cause premature aging, but the reasons are still unclear. Most cases of Cockayne syndrome (CS) are caused by recessive mutations in the CSB gene, yet some individuals with inherited mutations that cause complete loss of the CSB protein are nearly unaffected. The implication is that CS is not caused solely by loss of functional CSB protein, but by continued expression of CSB-related proteins or protein fragments.

The University of Washington researchers, led by Alan Weiner, had been investigating the normal function of the CSB gene when co-author John Newman stumbled across hints that the human CSB gene harbored a previously unsuspected guest. The guest was a "domesticated" PiggyBac transposon “ a formerly selfish "jumping gene" that had settled into the CSB gene over 40 million years ago before marmosets diverged from humans. As a result, the CSB gene began making two equally abundant products “ the normal CSB protein, and a fusion protein in which the beginning of the CSB protein was fused to the DNA transposase encoded by the PiggyBac element. Interestingly, the fusion protein continued to be expressed in almost all CS patients, but not in the individual who was unaffected by a complete loss of the CSB protein.

The conserved fusion protein is clearly advantageous for the human species in the presence of the CSB protein, but potentially devastating for individuals in the absence of the CSB protein. As Newman remarks, "The discovery of the fusion protein complicates an already complicated situation. Now we have a whole new set of questions to answer."

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Fink examined members of two families who had progressive weakness and spasticity (tightness) in their legs, as well as muscle atrophy in their hands, shins and feet. James Albers, M.D., Ph.D., a U-M professor of neurology and an expert in neuromuscular disorders, studied nerve and motor function. Rainier performed genetic studies and determined that the gene for the condition was on a region of chromosome 19.

Mark Leppert, Ph.D., co-chair of human genetics at the University of Utah, and his team performed genetic analysis that confirmed this location and excluded other areas in the genome. Among the many genes in this region of chromosome 19, one gene stood out as particularly likely: the gene that encodes for NTE. Because of its known role in organophosphate-induced neurological disease, the NTE gene was considered an important candidate gene and was studied immediately.

Analysis showed that the affected people in each family had NTE gene mutations. These mutations altered a critical part of the NTE protein called the esterase domain. Fink has named the inherited condition NTE motor neuron disease. It begins in childhood and progresses slowly, with symptoms of weakness and spasticity in the legs and muscle atrophy in the hands and lower legs.

Next, Fink and his team want to learn if mutations in the NTE gene happen in other types of motor neuron disease such as ALS, and if the mutations make a person more vulnerable to neurological damage from organophosphate exposure. Fink's lab is currently using fruit flies as a model to study the NTE mutations, with the goal of finding treatments for people with motor neuron disease.

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