Linkage of a Gene Causing Familial Amyotrophic Lateral Sclerosis to Chromosome 21 and Evidence of Genetic-Locus Heterogeneity

TLDR

Amyotrophic lateral sclerosis is a progressive neurological disorder that leads to paralysis and death, and in a minority of cases it is inherited autosomal dominantly, offering a unique opportunity to use molecular genetics to localize the underlying defect. The study aimed to use molecular genetic techniques to localize the inherited defect in familial ALS and to discover the basic molecular defect causing motor‑neuron degeneration. The researchers mapped the disease gene to four DNA markers on the long arm of chromosome 21. Linkage analysis linked the ALS gene to markers on chromosome 21q, yielding a maximum lod score of 5.03 at 10 cM distal to marker D21S58, and revealed a significant probability (P < 0.0001) of genetic‑locus heterogeneity.

Abstract

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. 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.