Positional cloning of the genetic defect causing Hereditary Neuralgic Amyotrophy (HNA)

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Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominant recurrent focal neuropathy. Patients suffer from recurrent episodes of painful brachial plexus neuropathy with muscle weakness and atrophy. Attacks are often preceded by unspecific infections suggesting involvement of the immune system in the pathogenesis of HNA. For these reasons, HNA could be a model for more common non-hereditary immune-mediated peripheral neuropathies. HNS shows genetic linkage with markers on chromosome 17q25. We and others have defined a 3,5 cM candidate region. We have constructed a complete sequence ready P1- and Bacterial Artificial Chromosome (PAC/BAC) clone contig of the candidate region and mapped 22 transcripts on it. The aim of the proposed research project is the identification of the genetic defect causing HNA. The cornerstones of our strategy are: DNA sequencing of the HNA candidate region in collaboration with the Whitehead Institute. Gene identification using computational methods. Confirmation and structural analysis of predicted genes and known expressed sequence tags (ESTs). Mutation analysis in our chromosome 17 linked HNA families by direct DNA sequencing.