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

Abstract

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.

Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy

“…These duplications are heterogeneous in nature, varying in size and location. However, all of the duplications encompass the 645 bp exon, and lymphoblastoid cell lines from affected individuals express modified protein products similar to those previously observed in the founder pedigrees 13. These data further support the hypothesis that alterations of the proline-rich region of SEPT9 play a role in the pathogenesis of HNA.…”

“…Array CGH was performed using a custom oligonucleotide array consisting of 385 000 isothermal probes (Roche NimbleGen, Inc., Madison, Wisconsin, USA) as previously described 13. The array included 1311 probes spanning a 300 kb region encompassing the SEPT9 gene (chr17: 72 800 000–73 100 000) with approximately one probe every 229 bp.…”

“…Blots were probed with anti-SEPT9 isoforms 1–3 and 5/6-reactive antibodies or an anti-SEPT9_i1-specific antibody as previously described 13 17. An anti-actin antibody (Sigma, St Louis, Missouri, USA) was used as a control to verify equivalent loading.…”

Septin 9 amplification and isoform-specific expression in peritumoral and tumor breast tissue

“…This is relevant for several reasons. SEPT9 mutations have been linked to HNA in which three common hotspot mutations and a common exonic duplication in North American HNA families have been reported (Kuhlenbaumer et al, 2005;Landsverk et al, 2009). However, the mechanism by which SEPT9 mutations cause HNA remains unknown (Sudo et al, 2007).…”

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

“…For example, Landsverk et al identified the gene causing a hereditary neuropathy (hereditary neuralgic amyotrophy [HNA]) that attacks the muscles responsible for controlling the movement of shoulders and arms 65 . In addition, Florian Thomas MD (St. Louis University, St. Louis, USA) and his international team have uncovered three different genetic mutations specific to dominant intermediate CMT neuropathy type C, a form of CMT disease 66 .…”