Researchers Discover Gene Mutations Linked With A Type Of Chronic Pain And Weakness Syndrome

HNA may first appear in the childhood or teen years, and lead torecurring episodes of severe, sudden onset pain in the arms andshoulders as well as weakness, loss of sensation, and muscle wasting.Episodes are often triggered by an infection, an immunization,childbirth, or overworking the arms and shoulders. Nerve inflammationand changes in the blood suggest that problems with the person's immuneresponse are contributing to the episode. The on again/off again courseof the condition, and the environmental triggers, are unusual amonginherited nerve disorders.

An associated aspect of the disorder in some individuals is facialfeatures -- a long, slender face and narrow, close-set eyes slantingupward -- reminiscent of portraits by the early 20th-century Italianpainter Modigliani, according to Phillip F. Chance, MD, professor ofpediatrics and neurology at the University of Washington in Seattle,whose laboratory first located the gene for this disorder to chromosome17 in 1996.

Twenty-seven medical scientists at universities in Germany, Belgium,the United States, Finland, and Spain conducted the research to findthe specific gene responsible for HNA. The lead authors of the study,which appears in the Sept. 25 edition of Nature Genetics, include Dr.Gregor Kuhlenbaumer of the University of Munster, Dr. Vincent Timmermanof the University of Antwerp, and Dr. Mark C. Hannibal and Dr. PhillipChance, both from the Division of Genetics and Developmental Medicineat the University of Washington.

By studying several multigenerational families who had severalrelatives with HNA, the researchers identified mutations in a genenamed septin-9 ( known as SEPT9). Cells from a variety of life forms,ranging from yeast to fruit flies to humans, contain septins. Septinsform protein filaments that provide the internal scaffolding of cells,and play key roles in the process by which cells divide. Out-of-controlseptins are implicated in certain abnormal cell divisions that lead totumor formation, including breast cancer. Cells depleted of SEPT9 oftenfail to complete normal cell division. HNA is the first genetic diseasefound to be caused by a mutation in a gene of the septin family.

According to the authors of the SEPT9 gene mutations study,SEPT9 has particular structures that distinguish it from all otherseptins, but the significance and function of these structures is asyet unknown. Future research on the SEPT9 gene and its mutations maylead to a better understanding of the normal function of the gene andits protein products. Scientists also hope to learn how the mutatedgene contributes to the development of specific facial features beforebirth and is later triggered to produce the nerve disorder, and why thedisease goes through exacerbations and remissions.

The research on the genetic mutations of SEPT9 was supported by grantsfrom the Deutsche Forschungsgemeinschaft, the Neuropathy Association,the National Institutes of Health, the Veterans Affairs Research Fund,the University of Antwerp, the Fund for Scientific Research, theInteruniversity Attraction Poles program of the Belgian Federal SciencePolicy Office, and the Medical Foundation Queen Elizabeth.