Duclos F, Rodius F, Wrogemann K, Mandel J L, Koenig M
Laboratoire de Génétique Moléculaire du CNRS, Unité INSERM 184, Faculté de Médecine et Centre Hospitalier Régional et Universitaire, Strasbourg, France.
Hum Mol Genet. 1994 Jun;3(6):909-14. doi: 10.1093/hmg/3.6.909.
Friedreich ataxia is a severe neurodegenerative autosomal recessive disorder of unknown biochemical defect. The Friedreich ataxia locus (FRDA) is tightly linked to the centromeric side of the D9S5 locus. We have used 'exon-trapping' to identify two new genes, approximately 100 and 200 kb centromeric to D9S5, respectively. One gene appears ubiquitously expressed while the other is prominently expressed in muscle. The ubiquitous transcript codes for a protein containing a 20 aa repeat reminiscent of simple repeats found in several ribonucleoproteins. Using the single-strand conformation polymorphism (SSCP) procedure, we searched for mutations in affected patients in the coding sequence of the two genes, as well as in a gene that we had previously identified in the same region. Eight polymorphic DNA changes but no causative mutations were found, suggesting that the genes are not candidates for Friedreich ataxia. The discovery of a simple sequence repeat polymorphism in the most centromeric gene allowed the localization within that gene of the breakpoint of a previously described recombination in a Friedreich ataxia family, therefore excluding the two distal genes from the FRDA region. The lack of causative mutations in the three genes and the position of the recombination further delineate the FRDA locus to a 300 kb interval.
弗里德赖希共济失调是一种严重的神经退行性常染色体隐性疾病，其生化缺陷不明。弗里德赖希共济失调基因座（FRDA）与D9S5基因座着丝粒侧紧密连锁。我们利用“外显子捕获”技术分别在D9S5着丝粒方向约100 kb和200 kb处鉴定出两个新基因。一个基因似乎在各处均有表达，而另一个则在肌肉中显著表达。普遍存在的转录本编码一种含有20个氨基酸重复序列的蛋白质，这让人联想到在几种核糖核蛋白中发现的简单重复序列。我们使用单链构象多态性（SSCP）方法，在受影响患者中搜索这两个基因以及我们先前在同一区域鉴定出的一个基因的编码序列中的突变。结果发现了8个多态性DNA变化，但未发现致病突变，这表明这些基因不是弗里德赖希共济失调的候选基因。在最着丝粒的基因中发现的一个简单序列重复多态性，使得能够在该基因内定位一个弗里德赖希共济失调家族中先前描述的重组断点，从而将FRDA区域内的两个远端基因排除在外。这三个基因中缺乏致病突变以及重组的位置进一步将FRDA基因座限定在一个300 kb的区间内。
