Original Article
Linkage of a Gene Causing Familial Amyotrophic Lateral Sclerosis to Chromosome 21 and Evidence of Genetic-Locus Heterogeneity
N Engl J Med 1991; 324:1381-1384May 16, 1991
- Abstract
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. 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.
Methods and Results.
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. (N Engl J Med 1991; 324:1381–4.)
Media in This Article
Figure 1
Multipoint Linkage Analysis of Familial Amyotrophic Lateral Sclerosis and Three Chromosome 21 Markers (D21S1/S11, APP, and D21S58) Spanning 21q21.1 to q22.3.Figure 2
Cosegregation of Chromosome 21 Markers with Familial Amyotrophic Lateral Sclerosis in One Pedigree (with Sex and Number Altered for Confidentiality).Article Activity
- Article
A MYOTROPHIC lateral sclerosis, often referred to as Lou Gehrig's disease, motor neuron disease, or Charcot's syndrome, is a devastating paralytic disorder with onset in adulthood, caused by degeneration of large motor neurons of the brain and spinal cord.1 It causes generalized and progressive wasting and weakness of skeletal muscles2 and usually results in death within five years.2 Currently there is no treatment to prevent this disease or to alter its unremitting course. Its annual incidence is similar to that of multiple sclerosis and more than five times that of Huntington's disease.3 Since the average duration of life after the clinical onset of amyotrophic lateral sclerosis is only three years, more adults die of it every year than of multiple sclerosis or Huntington's disease.
Although the pathophysiologic process of amyotrophic lateral sclerosis remains unknown, 5 to 10 percent of cases are familial,4 5 6 suggesting a genetic cause. Familial amyotrophic lateral sclerosis usually occurs in several generations of a family, with the disorder apparently inherited as an autosomal dominant trait with age-dependent penetrance.4 5 6 7 8 9 10 We used genetic-linkage analyses of 23 pedigrees with the familial form to identify the chromosomal location of a primary gene defect causing the disorder. Our results suggest that in a subgroup of these families, the disease may be caused by mechanisms other than a mutation at this locus.
Methods
Family Data
We analyzed several generations of 23 families (including 7 with previously published pedigrees11 , 12) with an autosomal dominant mode of inheritance of familial amyotrophic lateral sclerosis. Family members of both sexes were affected. The mean (±SD) age at the onset of symptoms was 47 ±13.6 years; the earliest symptoms were noted at the age of 15 years and the latest at 77. The mean duration of illness was 3.14±2.36 years. The male-to-female ratio was 1.3:1. Blood samples were obtained from 510 family members (including 60 who were affected or were obligate gene carriers) after they gave informed consent. All the families were of European ancestry.
The diagnosis of amyotrophic lateral sclerosis was established by at least one neurologist and was based on the standard diagnostic criteria2 of appropriate history, clinical findings, and electromyographic findings. Every patient had a family history of the disease and a syndrome of progressive weakness without any evidence of sensory, cerebellar, or cognitive impairment. The hallmark of diagnosis was lower-motor-neuron involvement, as manifested by weakness, atrophy, fasciculations, normal results on sensory and motor conduction studies, and electrophysiologic evidence of diffuse denervation and reinnervation. Upper-motor-neuron signs of spasticity, brisk deep-tendon reflexes, or extensor plantar responses were not present in any patient. Family members with only lower-motor-neuron disease and a family history of amyotrophic lateral sclerosis were also considered to be affected since variability of upper-motor-neuron signs is known to occur within families. Intrafamilial variability in the degree of pathologic involvement of the spinal cord was also observed in the corticospinal tract, the posterior column, and Clarke's column. Medical records, including autopsy reports (when available), were used to establish the diagnosis in dead family members.
DNA-Marker Analysis
DNA was extracted from lymphoblasts, fibroblasts, whole blood, or frozen autopsy tissue according to previously published protocols.12 DNA samples of 5 to 15 μg were digested with DNA endonucleases, separated in 1 percent agarose gels by electrophoresis, transferred to nylon-backed membranes, and hybridized to Radio-labeled DNA probes according to previously described methods.12 Autoradiographic bands were visually scored for marker alleles. Information on both the markers and the pedigrees was entered into computer files for analysis.
Linkage Analysis
The MLINK13 and LINKMAP13 subprograms of the computer program LINKAGE13 (version 4.9) were used to calculate the odds for or against linkage of the DNA markers to the locus for familial amyotrophic lateral sclerosis. Evidence of linkage is expressed as a lod score14 (the log10 of the odds of linkage); a lod score of 3 or higher is considered to indicate a significant probability of linkage, and a lod score of –2 or lower a significant probability that there is no linkage. The MLINK subprogram was used to calculate pair-wise lod scores between each DNA marker and the disease locus, and the subprogram LINKMAP was used to compute four-locus multipoint lod scores. The confidence interval for the recombination fraction (Θ) at the maximum lod score was calculated by subtracting 1 lod unit from the maximum lod score (z).15 The allele frequencies of the DNA markers and the intermarker recombination fractions (genetic distance) used in the analyses were obtained from published sources.16 , 17 Equal recombination fractions were used for male and female subjects. Because some haplotypes for the complex markers D21S1 /S 11 and D21S52 occur more frequently than others, known disequilibrium values were used in the analyses.18 The allele frequencies derived from the study of unrelated members of the families did not differ significantly from the published frequencies. When sufficient data on the genotypes of spouses and children were available, the genotypes of dead members known to be affected were inferred from those of their offspring. The probability of having inherited the disease was assigned to members at risk on the basis of the age-at-onset curve calculated from data on 79 affected members. The age at onset was defined in relation to the first clinical symptom. Using the mean age at onset in affected members, we constructed a normal distribution of the ages at onset. Penetrance of the gene for familial amyotrophic lateral sclerosis was estimated to be 90 percent by the age of 70.
Heterogeneity Analysis
Phenotypically homogeneous disorders can be caused by genetic defects in different genes. Statistical tests can sometimes identify such genetic heterogeneity even when clinical or biochemical evidence of heterogeneity is lacking. Such tests are especially valuable when data from multiple families are examined to establish linkage. We used the HOMOG (version 2.5)14 computer program to perform these computations.
Results
Over 100 polymorphic markers were examined for linkage to familial amyotrophic lateral sclerosis, which led to the exclusion of many regions of the genome12; however, several moderately positive lod scores were obtained for chromosome 21 markers.19 , 20 Further examination of these markers was performed on the full set of data on the 23 kindreds.
Positive lod scores were obtained in the two-point linkage analyses of each of the four chromosome 21 DNA markers — D21S52, D21S1 /S 11, APP (amyloid precursor protein), and D21S58 — and the locus for familial amyotrophic lateral sclerosis (Table 1Table 1
Pairwise Lod Scores for Familial Amyotrophic Lateral Sclerosis, According to Chromosome Locus.). The highest lod score, 2.89 at a recombination fraction (Θ) of 0.15 obtained with D21S1/S11, was not high enough to prove linkage (lod score ≥3). We therefore employed multipoint analysis13 to examine linkage of the disorder to this set of tandemly linked chromosome 21 markers (D21S52, D21S1/S11, APP, and D21S58). This simultaneous analysis maximized the information obtainable from the data set. The results of the multipoint analysis demonstrated linkage of a locus for familial amyotrophic lateral sclerosis to chromosome 21q (Fig. 1Figure 1Multipoint Linkage Analysis of Familial Amyotrophic Lateral Sclerosis and Three Chromosome 21 Markers (D21S1/S11, APP, and D21S58) Spanning 21q21.1 to q22.3.). The maximum lod score of 5.03 was obtained 10 centimorgans (cM) distal (telomeric) to D21S58. The highest lod score for a single family was 2.58. An overlapping multipoint map with D21S52, D21S1/S11, and APP was also analyzed (data not shown), and a peak lod score of 3.66 was obtained 11 cM distal to APP. To assess the effects of the age curve on the analysis, we shifted the mean age at onset upward by 20 years, which reduced the peak multipoint lod score to 2.82. This result indicates that a substantial portion of the linkage data was derived from members who were older and at risk but unaffected. An example of cosegregation of familial amyotrophic lateral sclerosis with chromosome 21 markers is shown in Figure 2Figure 2Cosegregation of Chromosome 21 Markers with Familial Amyotrophic Lateral Sclerosis in One Pedigree (with Sex and Number Altered for Confidentiality)..Examination of the family-specific lod scores revealed that most of the positive linkage information was derived from a subgroup of the families. Consequently, we used the HOMOG program14 to test the null hypothesis that all the families in our data set had linkage to chromosome 21 (test for homogeneity). The likelihood of heterogeneity approached statistical significance (P = 0.06) on analysis of the linkage data for D21S58, the DNA marker most closely linked to the locus for familial amyotrophic lateral sclerosis. Analysis of the multipoint lod scores revealed a significant probability of heterogeneity (P<0.0001), thus rejecting the null hypothesis of homogeneity and defining at least two genetic subgroups of families. The best estimate for the proportion of families with linkage to chromosome 21 was 0.55 (95 percent confidence interval, 0.20 to 0.93). This finding clearly demonstrates genetic heterogeneity in familial amyotrophic lateral sclerosis. There were no consistent differences in phenotype between the families with linkage and those without it.
Examination of the lod score for the families in which the gene for familial amyotrophic lateral sclerosis was most likely to be linked to chromosome 21 produced an optimal estimate for the position of the gene. The odds were approximately 54 to 1 that the gene's location was telomeric to APP, and 2884 to 1 that it was telomeric to D21S1/S11. This narrowed its most likely location to a region of approximately 10 cM that included the locus for D21S58.
Discussion
For the past seven years an extensive international effort has been organized to identify enough families with familial amyotrophic lateral sclerosis so that linkage analysis would be feasible, since potentially informative pedigrees are very difficult to find. Even in large pedigrees few affected members are available for testing,12 primarily because the disorder occurs late in life and patients have a mean survival of only three years. Our results indicate that in spite of these difficulties, linkage analysis can be a powerful technique.
Although our results are very convincing, they would be more so if a lod score of 3 or more could be generated independently from study of a single family. It may be possible to obtain such a result through the use of highly polymorphic probes close to the locus for familial amyotrophic lateral sclerosis. Recent studies of schizophrenia and bipolar illness indicate that the results of linkage analysis of diagnostically complex disorders should be interpreted with caution and that linkage should be verified independently of the original data. There are two reasons why these factors are not of major concern in our study. First, the diagnosis of amyotrophic lateral sclerosis is much more definitive than that of psychiatric disorders. Second, the results of our study of 23 families were based on linkage analysis of two subgroups of families in which the status of members and the diagnosis were ascertained independently at separate centers.
We used linkage analysis to establish genetic linkage between a gene causing familial amyotrophic lateral sclerosis and DNA markers from chromosome 21q22.1–22.2.21 This linkage clearly establishes the genetic contribution to this disorder and provides a crucial step toward understanding its pathophysiology. Furthermore, the evidence that familial amyotrophic lateral sclerosis may be a heterogeneous disorder suggests that more than one molecular mechanism may be responsible, and that one or more additional loci causing it may reside elsewhere in the genome. It should now be possible to apply strategies for isolating the responsible gene on the basis of its location on chromosome 21. Clearly, additional and more informative markers (such as dinucleotide repeats) in the D21S58 region will be necessary to establish which families carry the chromosome 21 disease locus, and to define the location of the defect further.
The cloning of the gene for familial amyotrophic lateral sclerosis and the characterization of its mode of action should provide insight into the mechanism of motor-neuron degeneration. Since the familial form of the disease is clinically indistinguishable from the sporadic form, it is possible that very similar defects in cellular mechanism are responsible for both forms, with a genetic and an environmental origin, respectively. Thus, insights gained from the identification of the primary defect in the familial form may be relevant to the sporadic form and increase our understanding of both forms. Even though help for families with familial amyotrophic lateral sclerosis is not around the corner, we believe that the identification and analysis of the gene (or genes) responsible for this disorder will lead to the development of specific tests for accurate diagnosis and perhaps provide a rational basis for the prevention and treatment of this disease.
Supported by grants (PO-NS–21442 [T.S.], NS–20012 [J.F.G.], PO-NS–26630 [M.A.P.-V., T.S.]) from the National Institutes of Health, the Amyotrophic Lateral Sclerosis Association (T.S., R.T., G.R.), the Muscular Dystrophy Association of America (T.S., J.L.H., R.H.B., R.T., B.J.), the Muscular Dystrophy Association Regional ALS Centers (B.R.B., R.P.R., T.L.M.), the Pierre L. de Bourgknecht A.L.S. Research Foundation (R.H.B.), the Day Neuromuscular Research Center (R.H.B.), Cambridge Neuroscience Research Inc. (D.A.F.), the Howard Hughes Medical Institute (H.R.H.), the Muscular Dystrophy Association of Canada (D.A.F., G.R.), the Amyotrophic Lateral Sclerosis Society of Canada (G.R., D.A.F.), the Medical Research Council of Canada (G.R.), and the Les Turner ALS Foundation (T.S., B.J.).
We are indebted to the patients and their families for their assistance and cooperation; to Dr. W.G. Johnson for his assistance in linking two branches of a kindred; to Drs. L.T. Kurland, J. Zabrana-Noore, H. Mitsumoto, W. Bradley, J.C. Kincaid, R.E. McMichael, M. Koller, N. Dufrane, J. Leanders, and M. Viane, and Sharon Diamond, R.N., for providing help in studying familial amyotrophic lateral sclerosis; and to Mike Wilkinson, Eddy Hanson, Peggy Pate, and Helen Harbett for providing technical assistance.
Source Information
From Duke University Medical Center, Durham, N.C. (T.S., M.A.P.-V., A.J.J., W.-Y.H., J.B., G.D., A.D.R.); Northwestern University Medical School, Chicago (T.S., G.D.); the Center for Research in Neuroscience, McGill University, Montreal (D.A.F., G.R.); Massachusetts Institute of Technology, Cambridge, Mass. (P.S., H.R.H.); and Massachusetts General Hospital, Boston (D.A.F., J.L.H., G.R., P.S., D.M.-Y., J.F.G., R.H.B.). Address reprint requests to Dr. Siddique at the Department of Neurology, Searle 11–543, North-western University Medical School, 303 E. Chicago Ave., Chicago, IL 60611.
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The study collaborators were Raymond P. Roos, M.D. (University of Chicago, Chicago); David B. Williams, M.D., Ph.D., and Donald W. Mulder, M.D. (Mayo Clinic, Rochester, Minn.); Paul C. Watkins, S.M. (Life Technologies Inc., Gaithersburg, Md.); FaizurRahman Noore, M.B., B.S. (Westmead Hospital, Westmead, N.S.W., Australia); Garth Nicholson, M.B., B.S., Ph.D. (University of Sydney, Sydney, N.S.W., Australia); Rosalyn Reed, B.S.N. (Duke University Medical Center, Durham, N.C.); Benjamin R. Brooks, M.D. (University of Wisconsin, Madison); Barry Festoff, M.D. (University of Kansas, Kansas City); Jack P. Antel, M.D. (Montreal Neurologic Hospital, Montreal); Rup Tandan, M.D. (University of Vermont, Burlington); Theodore L. Munsat, M.D. (Tufts—New England Medical Center, Boston); Nigel G. Laing, Ph.D. (Australian Neuromuscular Research Institute, Nedlands, W.A.); John J. Halperin, M.D. (State University of New York, Stony Brook); Forbes H. Norris, M.D. (Pacific Medical Center, San Francisco); R. Van den Bergh, M.D., and Lorry Swerts, M.D. (University of Leuven, Leuven, Belgium); Rudolph E. Tanzi, Ph.D. (Massachusetts General Hospital, Boston); Burk Jubelt, M.D. (State University of New York, Syracuse); and Katherine D. Mathews, M.D., and E. Peter Bosch, M.D. (University of Iowa Hospitals, Iowa City).
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