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遗传的复发性局灶性神经病。患者患有反复发作的疼痛性臂丛神经病变，伴有肌肉无力和萎缩。攻击之前往往是非特异性感染，表明免疫系统参与HNA的发病机制。由于这些原因，HNA可能是更常见的非遗传性免疫介导的周围神经病变的模型。HNS与染色体17 q25上的标记显示遗传连锁。我们和其他人已经定义了一个3.5厘米的候选区域。我们构建了候选区域的完整序列就绪P1和细菌人工染色体（PAC/BAC）克隆重叠群，并在其上绘制了22个转录本。拟议研究项目的目的是鉴定导致HNA的遗传缺陷。我们战略的基石是：与Whitehead Institute合作对HNA候选区域进行DNA测序。使用计算方法的基因鉴定。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号染色体连锁的HNA家族进行突变分析。

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.