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

遗传性神经痛性肌萎缩症（HNA）是一种常染色体显性的复发性局灶性神经病。患者反复发作疼痛性臂丛神经病变伴肌肉无力和萎缩。发作前往往有非特异性感染，提示免疫系统参与了海航的发病机制。由于这些原因，海航可能成为更常见的非遗传性免疫介导的周围神经病变的模型。HNS与17q25染色体上的标记存在遗传连锁。我们和其他人已经定义了一个3.5 cM的候选区域。我们构建了候选区域P1-和细菌人工染色体（PAC/BAC）的完整序列，并在其上定位了22个转录本。拟建研究项目的目的是鉴定导致海航的遗传缺陷。我们战略的基石是：与怀特海研究所合作，对海航候选地区进行DNA测序。利用计算方法进行基因鉴定。预测基因和已知表达序列标签（est）的确认和结构分析。通过直接DNA测序对我们的17号染色体进行突变分析。

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.