Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy.

[neuralgic amyotrophy]

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 SEPT 9 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 SEPT 9 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 SEPT 9 transcript variants that span this duplication contain two in -frame repeats of this exon , and immunoblotting demonstrates larger molecular weight SEPT 9 protein isoforms . This exon also encodes for a majority of the SEPT 9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA .