Molecular genetic analysis of hereditary neuralgic amyotrophy.

摘要

Hereditary neuralgic amyotrophy (HNA) is a rare, autosomal dominant disease. It is a recurrent, focal neuropathy at the level of the brachial plexus or sometimes the lumbosacral plexus. Episodes are characterized by sharp pain, by weakness and atrophy of arm and shoulder muscles and are often preceded by a triggering event, e.g. infections, immunizations or parturition. Single HNA episodes strongly resemble the episodes of the non-familial, idiopathic neuralgic amyotrophy, also called Parsonage-Turner syndrome. In collaboration with the department of Neurology at the University of Münster, Germany and in the very end also with the Pediatrics Department at the University of Washington, we aimed at the positional cloning of the gene responsible for HNA.; By linkage analysis, we confirmed the HNA locus on chromosome 17q25. Sampling over 15 HNA families and using additional Short Tandem Repeat (STR) markers, we reduced the HNA locus to an interval of 7.6 cM, which had 3.5 cM in common with a published 4 cM HNA region. Further, we defined a 2.2 cM interval, based on an informative recombination in a healthy individual. By linkage studies in two other HNA families, we were able to demonstrate genetic heterogeneity of the classical HNA type. The second step was the physical mapping of the linkage interval. The construction of a clone contig using Yeast artificial chromosomes (YACs) failed due to insufficient coverage, internal deletions and chimerism. Using bacterial and P1-derived artificial chromosome (BAC and PAC) clones, we constructed a contiguous contig of maximum 2 megabases. The Whitehead Institute selected this contig for their chromosome 17 sequencing effort. Thirdly, we constructed a transcript map, annotated one fully sequenced BAC clone and excluded 6 known genes by direct DNA sequencing. Although we found several polymorphisms, we did not find a disease causing mutation.; Both a clinical questionnaire and diagnostic guidelines were designed in collaboration with neurologists and geneticists specialized in HNA. It is available at http://molgen-www.uia.ac.be/cmt/. With the high pace of the human genome project, exon- and gene prediction programs and other bioinformatic tools will certainly accelerate the identification and characterization of the culprit gene of HNA.