Pandolfo M, Sirugo G, Antonelli A, Weitnauer L, Ferretti L, Leone M, Dones I, Cerino A, Fujita R, Hanauer A
Istituto Neurologico C. Besta, Milan, Italy.
Am J Hum Genet. 1990 Aug;47(2):228-35.
Friedreich ataxia (FA) is an autosomal recessive degenerative disease of the nervous system of unknown biochemical cause. The FA gene has been shown to be in close linkage with the two chromosome 9 markers D9S5 and D9S15, and linkage disequilibrium between FA and D9S15 has been detected in French families by Hanauer et al. We used new highly informative markers at the above loci to analyze Italian FA families for linkage and linkage disequilibrium. The new markers were a three-allele BstXI RFLP at D9S5 (PIC = .55) and a six-allele microsatellite, typed by polymerase chain reaction, at D9S15 (PIC = .75). We obtained maximum lod scores of 8.25 between FA and D9S5, 10.55 between FA and D9S15, and 9.52 between D9S5 and D9S15, all at zero recombination. Our results, combined with those reported by other authors, reduce maxlod-1 (maximum lod score minus 1) confidence limits to less than 1.1 cM between FA and D9S5, 1.2 cM between FA and D9S15, and 1.4 cM between D9S5 and D9S15. Linkage disequilibrium with FA was found only for D9S15 when all families were evaluated but was also found for a D9S5/D9S15 haplotype in a subgroup of southern Italian families. We conclude that FA, D9S5, and D9S15 are tightly clustered and that studies of geographically restricted groups may reveal a limited number of mutations responsible for the disease in the Italian population. We present preliminary evidence from pulsed-field gel electrophoresis that D9S5 and D9S15 may be less than 450 kb apart. Linkage disequilibrium between FA and D9S15 suggests that the disease gene may be at an even shorter distance from this marker locus, which therefore represents a very good starting point for cloning attempts.
弗里德赖希共济失调（FA）是一种常染色体隐性神经系统退行性疾病，其生化病因不明。FA基因已被证明与9号染色体上的两个标记D9S5和D9S15紧密连锁，Hanauer等人在法国家族中检测到FA与D9S15之间存在连锁不平衡。我们使用上述位点上新的高信息含量标记，对意大利FA家系进行连锁和连锁不平衡分析。新标记分别是D9S5位点上的一个三等位基因BstXI限制性片段长度多态性（PIC = 0.55），以及通过聚合酶链反应分型的D9S15位点上的一个六等位基因微卫星（PIC = 0.75）。在零重组时，我们得到FA与D9S5之间的最大对数优势分数为8.25，FA与D9S15之间为10.55，D9S5与D9S15之间为9.52。我们的结果与其他作者报道的结果相结合，将最大对数优势分数减1（最大对数优势分数减去1）的置信区间缩小到FA与D9S5之间小于1.1厘摩，FA与D9S15之间为1.2厘摩，D9S5与D9S15之间为1.4厘摩。在评估所有家系时，仅发现D9S15与FA存在连锁不平衡，但在意大利南部家系的一个亚组中，D9S5/D9S15单倍型也与FA存在连锁不平衡。我们得出结论，FA、D9S5和D9S15紧密聚集，对地理上受限群体的研究可能会揭示出意大利人群中导致该疾病的有限数量的突变。我们提供了脉冲场凝胶电泳的初步证据，表明D9S5和D9S15之间的距离可能小于450千碱基对。FA与D9S15之间的连锁不平衡表明疾病基因可能与该标记位点的距离更近，因此这是克隆尝试的一个非常好的起点。
