title: 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.
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Landsverk
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Ruzzo
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Karen
authors.initials: K
authors.lastname: Buysse
authors.forename: Jillian G
authors.initials: JG
authors.lastname: Buchan
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Petty
authors.forename: Esther A
authors.initials: EA
authors.lastname: Peterson
authors.forename: Dana M
authors.initials: DM
authors.lastname: Knutzen
authors.forename: Karen
authors.initials: K
authors.lastname: Barnett
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.forename: Judy
authors.initials: J
authors.lastname: Caress
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Parry
authors.forename: Dianna
authors.initials: D
authors.lastname: Quan
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Gardner
authors.forename: Ming
authors.initials: M
authors.lastname: Hong
authors.forename: Zachary
authors.initials: Z
authors.lastname: Simmons
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Chance
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hannibal
mesh_terms: D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D020968:Brachial Plexus Neuritis / Q000235:genetics*; D020090:Chromosome Segregation; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D018703:Founder Effect; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020440:Gene Duplication; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009656:North America; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016364:Reading Frames / Q000235:genetics; D058112:Septins
chemical_list: D012333:RNA, Messenger; D020558:GTP Phosphohydrolases; C474315:SEPTIN9 protein, human; D058112:Septins