LINKAGE OF A GENE CAUSING FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS TO CHROMOSOME-21 AND EVIDENCE OF GENETIC-LOCUS HETEROGENEITY
LINKAGE OF A GENE CAUSING FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS TO CHROMOSOME-21 AND EVIDENCE OF GENETIC-LOCUS HETEROGENEITY
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DOI：
10.1056/nejm199105163242001
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发表时间：
1991-05-16
影响因子：
158.5
通讯作者：
ROSES, AD
中科院分区：
文献类型：
--
作者：
SIDDIQUE, T;FIGLEWICZ, DA;ROSES, AD
背景肌萎缩侧索硬化症是一种进行性神经系统疾病，通常导致瘫痪和死亡。尽管经过了世纪的研究，但至今仍没有发现该病的病因、治疗方法或预防手段。在少数病例中，该病是家族性的，以常染色体显性遗传特征遗传，具有年龄依赖性遗传。与肌萎缩侧索硬化症的散发形式相反，家族性形式提供了使用分子遗传技术定位遗传缺陷的机会。此外，这些研究有可能发现导致运动神经元变性的基本分子缺陷。方法和结果。我们评估了23个家族性肌萎缩侧索硬化症的基因连锁导致这种疾病的21号染色体长臂上的四个DNA标记。多点连锁分析表明这些标记与该基因连锁。最大lod得分- 5.03 -获得10厘摩远端（端粒）的DNA标记D21 S58。该家系存在显著的基因位点异质性（P < 0.0001）。导致家族性肌萎缩侧索硬化症的基因的定位提供了分离该基因并研究其功能的手段。从了解该基因的功能中获得的见解可能适用于设计合理的治疗方法，用于家族性和散发性疾病。
Background. Amyotrophic lateral sclerosis is a progressive neurologic disorder that commonly results in paralysis and death. Despite more than a century of research, no cause of, cure for, or means of preventing this disorder has been found. In a minority of cases, it is familial and inherited as an autosomal dominant trait with age-dependent penetrance. In contrast to the sporadic form of amyotrophic lateral sclerosis, the familial form provides the opportunity to use molecular genetic techniques to localize an inherited defect. Furthermore, such studies have the potential to discover the basic molecular defect causing motor-neuron degeneration.Methods and Results. We evaluated 23 families with familial amyotrophic lateral sclerosis for linkage of the gene causing this disease to four DNA markers on the long arm of chromosome 21. Multipoint linkage analyses demonstrated linkage between the gene and these markers. The maximum lod score - 5.03 - was obtained 10 centimorgans distal (telomeric) to the DNA marker D21S58. There was a significant probability (P < 0.0001) of genetic-locus heterogeneity in the families.Conclusions. The localization of a gene causing familial amyotrophic lateral sclerosis provides a means of isolating this gene and studying its function. Insight gained from understanding the function of this gene may be applicable to the design of rational therapy for both the familial and sporadic forms of the disease.