The long term objective of this proposal is to determine the molecular basis of hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) through the identification and characterization of the gene for this disorder. HNA is an autosomal dominant disorder associated with recurrent episodes of painful brachial plexus dysfunction. Individuals with HNA may suffer repeated episodes of intense pain, paralysis and sensory disturbances in an affected limb. The onset of HNA may be at birth or later in childhood. Usually the prognosis for recovery is favorable, however persons with HNA may have permanent residual neurologic dysfunction following an attack. The biochemical and molecular basis of HNA is unknown. The gene for HNA has been mapped to chromosome 17q24-25 with evidence for genetic homogeneity. Standard methods of human linkage analysis will be used to identify additional HNA pedigrees, carry out linkage studies aimed to refine the location of the HNA gene on chromosome 17q24-25, test candidate genes and if necessary, isolate a gene for HNA through positional cloning methods. Multiple HNA pedigrees will be ascertained to provide at least 100-200 informative matings for linkage analysis and assessment of genetic homogeneity. Genetic and physical methods will be used to narrow the region of the HNA locus to a 1-2 centimorgan interval, search for transcripts as candidate genes and identify mutations leading to HNA. Identification of the HNA gene will permit the assessment of its patterns of tissue distribution and developmental expression in addition to providing insights into the molecular and biochemical abnormalities leading to the HNA phenotype. Moreover, characterization of the HNA gene may have broader pathophysiological and therapeutic implications for more common idiopathic forms of brachial neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038181-01
Application #
2741290
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Nichols, Paul L
Project Start
1998-05-08
Project End
2002-03-31
Budget Start
1998-05-08
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Landsverk, Megan L; Weiser, Douglas C; Hannibal, Mark C et al. (2010) Alternative splicing of sept9a and sept9b in zebrafish produces multiple mRNA transcripts expressed throughout development. PLoS One 5:e10712
Collie, A M B; Landsverk, M L; Ruzzo, E et al. (2010) Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy. J Med Genet 47:601-7
Hannibal, M C; Ruzzo, E K; Miller, L R et al. (2009) SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy. Neurology 72:1755-9
Landsverk, Megan L; Ruzzo, Elizabeth K; Mefford, Heather C et al. (2009) Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy. Hum Mol Genet 18:1200-8
Laccone, F; Hannibal, M C; Neesen, J et al. (2008) Dysmorphic syndrome of hereditary neuralgic amyotrophy associated with a SEPT9 gene mutation--a family study. Clin Genet 74:279-83
Bennett, Craig L; Parisi, Melissa A; Eckert, Melissa L et al. (2004) Joubert syndrome: a haplotype segregation strategy and exclusion of the zinc finger protein of cerebellum 1 (ZIC1) gene. Am J Med Genet A 125A:117-24; discussion 117
Street, V A; Bennett, C L; Goldy, J D et al. (2003) Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60:22-6
Blair, Ian P; Gibson, Roxanne R; Bennett, Craig L et al. (2002) Search for genes involved in Joubert syndrome: evidence that one or more major loci are yet to be identified and exclusion of candidate genes EN1, EN2, FGF8, and BARHL1. Am J Med Genet 107:190-6
Watts, Giles D J; O'Briant, Kathy C; Chance, Phillip F (2002) Evidence of a founder effect and refinement of the hereditary neuralgic amyotrophy (HNA) locus on 17q25 in American families. Hum Genet 110:166-72
Street, Valerie A; Goldy, Jeff D; Golden, Alana S et al. (2002) Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am J Hum Genet 70:244-50

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