Siddique T, Figlewicz D A, Pericak-Vance M A, Haines J L, Rouleau G, Jeffers A J, Sapp P, Hung W Y, Bebout J, McKenna-Yasek D
Duke University Medical Center, Durham, N.C.
N Engl J Med. 1991 May 16;324(20):1381-4. doi: 10.1056/NEJM199105163242001.
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.
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 less than 0.0001) of genetic-locus heterogeneity in the families.
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.
肌萎缩侧索硬化症是一种进行性神经疾病，通常会导致瘫痪和死亡。尽管经过了一个多世纪的研究，但尚未找到该疾病的病因、治愈方法或预防手段。在少数情况下，它是家族性的，以常染色体显性性状伴年龄依赖性外显率遗传。与散发性肌萎缩侧索硬化症不同，家族性形式为利用分子遗传学技术定位遗传缺陷提供了机会。此外，此类研究有可能发现导致运动神经元变性的基本分子缺陷。
我们评估了23个患有家族性肌萎缩侧索硬化症的家庭，以确定导致该疾病的基因与21号染色体长臂上的四个DNA标记之间的连锁关系。多点连锁分析表明该基因与这些标记之间存在连锁关系。在DNA标记D21S58远端（端粒方向）10厘摩处获得了最大对数优势分数——5.03。这些家庭中存在基因位点异质性的概率显著（P小于0.0001）。
导致家族性肌萎缩侧索硬化症的基因定位为分离该基因并研究其功能提供了一种方法。通过了解该基因的功能所获得的见解可能适用于设计针对该疾病家族性和散发性形式的合理治疗方案。
