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NEUROLOGY 2009;72:1755-1759
© 2009 American Academy of Neurology

SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy

M. C. Hannibal, MD, PhD, E. K. Ruzzo, BS, L. R. Miller, BS, B. Betz, BS, J. G. Buchan, BS, D. M. Knutzen, MS, K. Barnett, MS, M. L. Landsverk, PhD, A. Brice, MD, E. LeGuern, MD, PhD, H. M. Bedford, MD, B. B. Worrall, MD, MSc, S. Lovitt, MD, S. H. Appel, MD, E. Andermann, MD, PhD, T. D. Bird, MD and P. F. Chance, MD

Authors’ affiliations are listed at the end of the article.
From the Departments of Pediatrics (M.C.H., E.K.R., L.R.M., B.B., J.G.B., D.M.K., K.B., M.L.L., P.F.C.), Neurology (T.D.B., P.F.C.), and Medicine (T.D.B.), University of Washington School of Medicine, Seattle; Seattle Children’s Hospital (M.C.H., P.F.C.); Geriatric Research Education and Clinical Center (T.D.B.), VA Puget Sound Health Care System, Seattle; Department of Genetics and Cytogenetics (A.B., E.L.), INSERM, UMR S679, Pierre and Marie Curie Paris VI University, Pitié-Salpêtriére Medical School, AP-HP, Pitié-Salpêtriére Hospital, Paris, France; Genetics Programme (H.M.B.), North York General Hospital, Toronto, Ontario, Canada; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia Health System, Charlottesville; Department of Neurology (S.H.A), Methodist Neurological Institute (S.L.), Houston, TX; and Departments of Neurology & Neurosurgery and Human Genetics (E.A.), Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Dr. Mark C. Hannibal, Neurogenetics Laboratory, 1959 NE Pacific St., Health Sciences RR236, Box 356320, Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195-6320 mhanni{at}u.washington.edu

Background: Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder that manifests as recurrent, episodic, painful brachial neuropathies. A gene for HNA maps to chromosome 17q25.3 where mutations in SEPT9, encoding the septin-9 protein, have been identified.

Objective: To determine the frequency and type of mutations in the SEPT9 gene in a new cohort of 42 unrelated HNA pedigrees.

Methods: DNA sequencing of all exons and intron-exon boundaries for SEPT9 was carried out in an affected individual in each pedigree from our HNA cohort. Genotyping using microsatellite markers spanning the SEPT9 gene was also used to identify pedigrees with a previously reported founder haplotype.

Results: Two missense mutations were found: c.262C>T (p.Arg88Trp) in seven HNA pedigrees and c.278C>T (p.Ser93Phe) in one HNA pedigree. Sequencing of other known exons in SEPT9 detected no additional disease-associated mutations. A founder haplotype, without defined mutations in SEPT9, was present in seven pedigrees.

Conclusions: We provide further evidence that mutation of the SEPT9 gene is the molecular basis of some cases of hereditary neuralgic amyotrophy (HNA). DNA sequencing of SEPT9 demonstrates a restricted set of mutations in this cohort of HNA pedigrees. Nonetheless, sequence analysis will have an important role in mutation detection in HNA. Additional techniques will be required to find SEPT9 mutations in an HNA founder haplotype and other pedigrees.

Abbreviations: HNA = hereditary neuralgic amyotrophy; SNP = single nucleotide polymorphism; STR = short tandem repeat; UTR = untranslated region.

Supplemental data at www.neurology.org

Supported by funds from the NIH (National Institute of Neurological Disorders and Stroke), NS38181 (P.F.C. and M.C.H.); The Neuropathy Association, New York, NY (M.C.H. and P.F.C.); and the Allan and Phyllis Treuer Endowed Chair for Genetics and Development (P.F.C.).

Disclosure: Dr. Chance has received Speaker’s Bureau honoraria from Athena Diagnostics, Inc. Dr. Bird has received licensing fees from Athena Diagnostics, Inc.

Medical Device: Gentra Puregene Blood Kit (Qiagen, Valencia, CA).

Received August 11, 2008. Accepted in final form February 13, 2009.






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