Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity

Teepu Siddique*, Denise A. Figlewicz, Margaret A. Pericak-Vance, Jonathan L. Haines, Guy Rouleau, Anita J. Jeffers, Peter Sapp, Wu Yen Hung, Jacqueline Bebout, Diane Mckenna-Yasek, Gang Deng, H. Robert Horvitz, James F. Gusella, Robert H. Brown, Allen D. Roses, Raymond P. Roos, David B. Williams, Donald W. Mulder, Paul C. Watkins, FaizurRahman NooreGarth Nicholson, Rosalyn Reed, Benjamin R. Brooks, Barry Festoff, Jack P. Antel, Rup Tandan, Theodore L. Munsat, Nigel G. Laing, John J. Halperin, Forbes H. Norris, R. Van Den Bergh, Lorry Swerts, Rudolph E. Tanzi, Burk Jubelt, Katherine D. Mathews, E. Peter Bosch

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

376 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1381-1384
Number of pages4
JournalNew England Journal of Medicine
Issue number20
Publication statusPublished - 16 May 1991
Externally publishedYes


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