Human Molecular Genetics Advance Access originally published online on January 12, 2009
Human Molecular Genetics 2009 18(7):1200-1208; doi:10.1093/hmg/ddp014
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Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy
1 Department of Pediatrics 2 Department of Genome Sciences 3 Department of Neurology 4 Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA 5 Seattle Children's Hospital, Seattle, WA 98105, USA 6 Howard Hughes Medical Institute, Seattle, WA 98195, USA 7 Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA 8 Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA 9 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 10 Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA 11 Department of Neurology, University of Colorado Denver, Aurora, CO 80045, USA 12 Department of Neurology, Veterans Administration Hospital and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA 13 Group Health Bellevue Medical Center, Bellevue, WA 98004, USA 14 Department of Neurology, Penn State College of Medicine, Hershey Medical Center, Hershey, PA 17033, USA 15 Center for Medical Genetics, Ghent University Hospital B-9000, Ghent, Belgium
* To whom correspondence should be addressed at: HSB RR247 Box 356320, 1959 NE Pacific St, Seattle, WA 98195, USA. Tel: +1 2062215465; Fax: +1 2062215132; Email: mhanni{at}u.washington.edu or mark.hannibal{at}seattlechildren.org
Received August 27, 2008; Accepted January 5, 2009
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.