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Modifier gene controls severity of neurological disease in mice

15.08.2003


Also found in humans - could explain why some get sicker than others

University of Michigan scientists have discovered a gene that turns a chronic inherited neurological disorder – which produces tremor and muscle weakness in laboratory mice – into a lethal disease that paralyzes and kills them within a few weeks of birth.

Called Scnm1 for sodium channel modifier 1, the gene is one of a small group of recently discovered modifier genes that interact with other genes to alter the physical effects of inherited diseases.



There are many inherited diseases – including cystic fibrosis, amyotrophic lateral sclerosis (ALS) and epilepsy – where symptoms vary widely, even between members of the same family. Understanding how modifier genes work could help scientists solve a fundamental mystery of genetics: Why do people with identical genetic mutations often differ in the severity or age of onset of the same inherited disease?

"In our study with mice, we found that the severity of neurological defects caused by mutations in a gene called Scn8a are determined by another gene, Scnm1, which is located on a different chromosome," says Miriam Meisler, Ph.D., a professor of human genetics in the U-M Medical School. "Scnm1 is expressed in many human cells, which suggests that it could modify the severity of a wide range of inherited disorders in humans, including other neurological diseases."

Meisler conducted the study with David Buchner, a U-M graduate student, and Michelle Trudeau, a U-M research associate. Results will be published in the Aug. 15 issue of Science.

Meisler’s research focuses on sodium channel genes that control the flow of electrical signals between nerve and muscle cells. Mutations in sodium channel genes produce a variety of neurological disorders – including several types of epilepsy, ataxia, poor muscle coordination, paralysis and cardiac arrhythmias like long QT syndrome.

In their study, U-M researchers used "black-6" or B6 mice – the most common type used in biomedical research – which contained a mutation in an important sodium channel gene called Scn8a.

Scn8a forms pores in nerve cell projections called axons and dendrites – allowing sodium ions to flow through – and rapidly opens and closes the pores to initiate and cut off the electrical signal. Mice with mutated forms of Scn8a have a range of neurological defects and movement disorders, depending on their specific mutation.

"We used B6 mice with a splice site mutation in Scn8a that affects the amount of protein produced by the gene," says Buchner, who is first author on the paper. "When the genetic code for Scn8a is transcribed to RNA, the mutation causes it to frequently skip two coding regions within the gene. Without those two coding regions, the cell produces a nonfunctional form of Scn8a protein."

"It’s not an all-or-nothing process," adds Trudeau, a co-author on the paper. "Occasionally the RNA transcripts are correctly assembled, but most of the time they are not. Fortunately, mice can survive as long as the amount of normal protein doesn’t fall below a minimum threshold."

If at least 50 percent of the Scn8a protein is functional, the mice appear perfectly normal, according to Buchner. If the amount of functional protein falls to 10 percent, mice have some degree of neurological deficit, but can still live a normal life span. But if protein levels dip below 5 percent, the mice are paralyzed and don’t survive more than one month after birth.

In a genome-based approach, U-M scientists identified the mouse mutation in the Scnm1 modifier gene by comparing the DNA sequence in B6 mice with data from the Human Genome Project. The B6 mouse gene contains a mutation called a premature stop codon, which blocks some of the genetic instructions needed to make normal Scnm1 modifier protein. As a result, the B6 gene is 20 percent shorter than the normal mouse or human gene.

"The B6 mutation doesn’t cause disease by itself, but produces a genetic susceptibility to mutations in other genes," Buchner explains.

Mice with two copies of the B6 variant of the modifier gene had just 5 percent of the normal amount of functional Scn8a protein and died soon after birth. "The mutation in Scnm1 reduces the amount of Scn8a protein below the minimum threshold required for normal neurological function," Meisler says.

To see if he could "rescue" B6 mice that had the lethal combination of mutations in Scn8a and Scnm1, Buchner injected a normal copy of the Scnm1 gene into fertilized mouse eggs. In two different experiments, Buchner was able to prevent paralysis and juvenile lethality.

When U-M scientists compared DNA in the Scnm1 mouse gene to sequenced DNA from the Human Genome Project’s databank, they found it closely matched the sequence of the human form of the sodium channel modifier gene.

"Now that we have identified the gene and the mechanism by which it works, as well as the precise chromosome location of the human gene, we can begin looking for interactions with other mutations associated with human neurological disorders like epilepsy," Meisler says. "This modifier is likely to interact with other types of genes, in addition to human sodium channels. If we can find a way to change the secondary effects of modifier genes, we may be able to minimize the impact of the original genetic defect."

The U-M study was funded by the National Institutes of Health.


###
Sally Pobojewski, pobo@umich.edu, 734-615-6912, or
Kara Gavin, kegavin@umich.edu, 734-764-2220


Sally Pobojewski | EurekAlert!
Further information:
http://www.med.umich.edu/1toolbar/whatsnew.htm

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