Sirugo G, Duclos F, Fujita R, Keats J B, Pandolfo M, Mandel J L, Koenig M
LGME-CNRS, U.184 INSERM, Faculté de Médecine, Strasbourg, France.
Biomed Pharmacother. 1994;48(5-6):219-24. doi: 10.1016/0753-3322(94)90136-8.
The Friedreich's ataxia locus (FRDA) is tightly linked to markers D9S5 and D9S15 located in 9q13-q21. Cumulated maximum lod scores between FRDA and D9S5 and between FRDA and D9S15 are above 36 and 61, respectively, at a recombination fraction of 0, indicating that recombination events needed to orient the search of the gene are very difficult to identify and ascertain. We have established a 1 Megabase PFGE map around D9S5 and D9S15 and isolated a corresponding 530 kb YAC contig. We found that the two markers are 260 kb apart. This result was surprising, since D9S5 and D9S15 were independently isolated, but in agreement with the strong linkage between the two loci (lod score > 35 at a recombination fraction of 0). Seven clusters of rare cutter enzyme sites (CpG islands), which are potential indicators of genes, were identified in the 1 Megabase region by PFGE analysis and YAC mapping. The search for genes around the CpG islands is in progress. To map the Friedreich ataxia locus in the absence of clearly identified recombination events, we chose an alternative approach based on haplotype analysis of patients from small populations with precise geographic and historical origins, such as the Louisiana-Acadians, deported from Nova-Scotia about 150 years ago and who remained isolated for historical and cultural reasons. In this population, a single mutation, associated with a specific haplotype may account for the majority of Friedreich ataxia cases. Haplotypes different from the major haplotype at one or the other extremity can indicate ancient recombinations.(ABSTRACT TRUNCATED AT 250 WORDS)
弗里德赖希共济失调基因座（FRDA）与位于9q13 - q21的标记D9S5和D9S15紧密连锁。在重组率为0时，FRDA与D9S5之间以及FRDA与D9S15之间的累积最大对数优势分数分别高于36和61，这表明确定寻找该基因所需的重组事件非常困难且难以确定。我们围绕D9S5和D9S15构建了一个1兆碱基的脉冲场凝胶电泳（PFGE）图谱，并分离出了一个相应的530千碱基的酵母人工染色体（YAC）重叠群。我们发现这两个标记相距260千碱基。这一结果令人惊讶，因为D9S5和D9S15是独立分离的，但与两个基因座之间的强连锁关系一致（在重组率为0时对数优势分数> 35）。通过PFGE分析和YAC图谱，在1兆碱基区域内鉴定出了七个稀有切割酶位点簇（CpG岛），它们是基因的潜在指示物。围绕CpG岛寻找基因的工作正在进行。为了在没有明确确定的重组事件的情况下绘制弗里德赖希共济失调基因座图谱，我们选择了一种基于对具有精确地理和历史起源的小群体患者进行单倍型分析的替代方法，例如大约150年前从新斯科舍被驱逐且因历史和文化原因一直保持隔离的路易斯安那阿卡迪亚人。在这个群体中，与特定单倍型相关的单个突变可能占弗里德赖希共济失调病例的大多数。在一个或另一个末端与主要单倍型不同的单倍型可能表明古老的重组事件。（摘要截选至250字）
