Original Article
Mapping of a Gene Causing Familial Mediterranean Fever to the Short Arm of Chromosome 16
N Engl J Med 1992; 326:1509-1513June 4, 1992
- Abstract
- Abstract
Background.
Familial Mediterranean fever is an autosomal-recessive disease characterized by acute attacks of fever with sterile peritonitis, pleurisy, or synovitis. The biochemical basis of the disease is unknown, but determining the chromosomal location of the gene for the disorder should be a first step toward defining the biochemical events.
Methods and Results.
As part of a systematic genome-wide search, we sought evidence of linkage between familial Mediterranean fever and chromosome 16 DNA markers in 27 affected non-Ashkenazi Jewish families from Israel. Two loci from the subtelomeric region of the short arm of chromosome 16 (16p) had lod scores sufficient to establish linkage (a score ≥3). One DNA marker (D16S84) gave a maximal lod score of 9.17 (odds of 109.17 to 1 in favor of linkage) at a recombination frequency (θ) of 0.04. A probe associated with the hemoglobin α complex (5'HVR) gave a maximal lod score of 14.47 at a θ of 0.06. Multipoint linkage analysis indicated that the following was the most likely gene order: the centromere, the gene for familial Mediterranean fever, D16S84, hemoglobin α, and the telomere. The maximal multipoint lod score was 19.86. There was a striking degree of homozygosity at chromosome 16p loci in the affected offspring of eight consanguineous couples.
Conclusions.
The gene that causes familial Mediterranean fever in non-Ashkenazi Jews maps to the short arm of chromosome 16. (N Engl J Med 1992;326:1509–13.)
Article Activity
- Article
Familial Mediterranean fever is a disorder characterized by intermittent attacks of fever with abdominal pain, pleurisy, or arthritis; its symptoms are not apparent between attacks. This inherited autosomal-recessive disease affects primarily members of non-Ashkenazi Jewish,1 Armenian,2 Turkish,3 and Middle Eastern Arab4 populations. The frequency of the disease gene among these populations is extraordinarily high, reaching 1 in 22 among Jews in North Africa and 1 in 14 among Armenians in Los Angeles.5 Until prophylaxis with daily oral colchicine was instituted, the disorder was a major cause of amyloidosis with renal failure among Turks and non-Ashkenazi Jews.1 , 3 , 6
Attacks of familial Mediterranean fever are characterized by a massive influx of polymorphonuclear leukocytes into the affected tissues.1 However, the biochemical and molecular causes of this disorder are unknown. Matzner et al. have proposed that it may be caused by a deficiency of an inhibitor of the fifth component of complement,7 , 8 but the inhibitor protein is incompletely characterized, and the gene that encodes this protein has not been cloned.9 The gene for familial Mediterranean fever is clearly not linked to the HLA complex.10 , 11
To study the molecular basis of the disease, we undertook a "reverse genetic" approach similar to the strategy used to identify the genes causing cystic fibrosis and several other genetic disorders.12 We studied DNA from 27 affected Israeli families for linkage between the disease-susceptibility gene and known genetic markers. Before the experiments reported here, we had examined more than 100 markers from 20 of the 23 pairs of human chromosomes.13 , 14 Our data excluded a number of candidate genes,15 as well as over one third of the human genome, as the site of the gene for familial Mediterranean fever. We had preliminary evidence of linkage to chromosome 17, but we were unable to confirm it.13 , 14 Therefore, we turned our attention to chromosomal regions not yet evaluated. In this report we present the results obtained with the use of two markers on the short arm of chromosome 16.
Methods
Study Families
Families were recruited from a clinic at the Sheba Medical Center, Tel-Hashomer, Israel. The Human Experimentation Committee at that institution approved the study, and participants gave informed consent. The data presented here pertain to 27 Israeli families of North African and Iraqi origin that contained a total of 180 members; 87 members had familial Mediterranean fever, which was diagnosed according to established clinical criteria.1 Unaffected members were included in the study only if they were more than 20 years old, since disease penetrance reaches 90 percent by this age in our study population.1 Paternity was confirmed with a number of highly polymorphic DNA markers. Ten families in this panel were consanguineous, including six first-cousin marriages (16 affected offspring) and two uncle—niece marriages (3 affected offspring).
Twenty milliliters of blood was obtained from each person and treated with heparin; the peripheral-blood lymphocytes were immortalized with Epstein–Barr virus according to standard techniques.16
DNA Probes
Plasmid DNA for pCMM65 (D16S84)17 was kindly provided by Dr. Peter O'Connell (Howard Hughes Medical Institute and University of Utah Medical School). The plasmid p5'HVR (highly variable region)18 hybridizes to a variable—copy-number, tandem-repeat array of a 57-bp sequence about 100 kb upstream from the hemoglobin α complex; plasmid DNA was obtained from the American Type Culture Collection.
Southern Blot Analysis
DNA was purified from cell lines by sodium dodecyl sulfate—proteinase K digestion, phenol—chloroform extraction, and ethanol precipitation.19 DNA from each family member was digested with appropriate restriction endonucleases, electrophoresed, and blotted onto nylon membranes.20 Whole plasmid or cosmid probes were labeled with phosphorus-32 by random hexadeoxyribonucleotide priming (Oligolabeling Kit, Pharmacia).21 Hybridizations were performed under standard conditions in the presence of human placental DNA (0.25 mg per milliliter).22 High-stringency washes were carried out with 0.1 × standard saline citrate—0.1 percent sodium dodecyl sulfate at 60°C. Autoradiography was performed with Kodak XAR-5 film for 1 to 10 days at -70°C with intensifying screens.
Linkage Analysis
We used the LINKAGE (version 5.1) package of computer programs23 to calculate lod scores. A lod score is defined as the logarithm, to the base 10, of the ratio of the odds in favor of linkage to the odds against linkage.24 A lod score of 3.0 (corresponding to an odds ratio of 1000:1) or more is considered evidence of linkage. Two-point lod scores were calculated for linkage between familial Mediterranean fever and individual DNA markers. Multipoint lod scores were determined with a computer program that calculated odds ratios in relation to more than one marker locus at a time. Lod scores were calculated for various possible recombination frequencies for the disease gene and marker loci. The frequency of recombination is denoted by θ; the value of θ for which the lod score was maximal would represent the most likely recombination frequency for the gene for familial Mediterranean fever and the marker locus. Approximate 95 percent confidence intervals for θ were obtained by determining recombination frequencies for which the lod score was the maximum minus 1.25 Recombination frequencies were transformed to map distances according to Kosambi's formula26; a recombination frequency of 1 percent corresponds to a map distance of 1 cM.
Computations were performed on a VAX 8650 computer at the National Cancer Institute Advanced Scientific Computing Laboratory (Frederick, Md.) or on a VAXStation 3100 Model 76 in our laboratory. Using the most current population-based data from the Sheba Medical Center, we constructed a model in which familial Mediterranean fever was considered an autosomal-recessive trait that had 95 percent penetrance in males and 70 percent penetrance in females and a gene frequency of 0.045. Map distances and allele frequencies were taken from published sources.27 28 29 30 For the probe 5'HVR, we assumed seven alleles of equal frequency.
Results
Two-Point Linkage Analysis
In our systematic search for the gene causing familial Mediterranean fever, one of the first chromosome 16 markers that we examined was D16S84, a two-allele polymorphism identified by probing TaqI-digested Southern blots with the plasmid pCMM65.17 The autoradiogram for one of our study families is shown in Figure 1Figure 1
Representative Autoradiograms of Southern Blots for Two Chromosome 16p Markers, D16S84 and Hemoglobin α Complex (HBA), in Two Families with Familial Mediterranean Fever. (D16S84). In this family, all three affected offspring were AB heterozygotes; the two unaffected offspring had the AA genotype. Therefore, in this family, one of the mother's A alleles and the father's B allele were inherited with the disease gene. Using the MLINK computer program,23 we found that the lod score for this family was 0.81 at a recombination frequency of 0.00. This means that the odds in favor of linkage are approximately 6.5:1 (10.081 = 6.5), given the genotypes in this family and assuming that there are no recombinations between the disease gene and the marker D16S84.In a similar fashion, lod scores were calculated for each of the families at various recombination frequencies. For each recombination frequency, the lod score for all of the families is the sum of the lod scores for the individual families. The total lod scores for various recombination frequencies are shown in Table 1.Table 1
Two-Point Lod Scores, According to Recombination Fraction, for Linkage between Familial Mediterranean Fever and Selected Chromosome 16 Markers in 27 Non-Ashkenazi Jewish Families.* The maximal lod score for these families was 9.17 at a recombination frequency of 0.04 (95 percent confidence interval, 0.00 to 0.11).Since D16S84 has been mapped to the terminal part of the short arm of chromosome 16,27 28 29 30 we sought another marker from this region to confirm our findings. The probe 5'HVR detects an RsIl restriction-fragment–length polymorphism associated with the hemoglobinα complex18 and is about 5 cM telomeric to D16S84. This marker is highly polymorphic; in the family represented in Figure 1, the four different parental alleles were discernible. In that family, paternal allele A (16.5 kb) and maternal allele B (3.9 kb) were associated with the carrier state of familial Mediterranean fever. Only offspring inheriting both alleles expressed the disease. The lod score for this single family, calculated at a recombination frequency of 0.00, was 0.88 (7.5:1 odds in favor of linkage). Table 1 summarizes the data on lod scores for the hemoglobinα locus in all the families. The overall maximal lod score for this marker was 14.47 at a recombination frequency of 0.06 (95 percent confidence interval, 0.02 to 0.11).
In certain areas of the genome, the rate of recombination during meiosis in males may differ from the rate in females. Near the telomere of the short arm of chromosome 16, recombination in males markedly exceeds that in females.27 28 29 30 Therefore, we calculated sex-specific recombination rates for familial Mediterranean fever and our two markers. For the marker D16S84, the recombination rate in males was roughly 1.5 times the rate in females (0.045 vs. 0.029). For the hemoglobin α marker, the excess of recombination in males was even more pronounced — an observed recombination rate of 0.116, as compared with 0.001 in females.
Multipoint Linkage Analysis
Two-point linkage analysis allows the estimation of recombination rates for familial Mediterranean fever and individual genetic markers. When there are two or more genetic markers in a given chromosomal region, and the rate of recombination between the genetic markers is known, it is possible to perform multipoint linkage analysis. This mathematical method compares the inheritance of a disease gene with the inheritance of multiple markers simultaneously and allows the gene to be located on the genetic map in relation to these markers.
Figure 2Figure 2
Location of D16S84 and Hemoglobin α Complex (HBA) on Chromosome 16 and Results of Multipoint Linkage Analysis of 27 Families with Familial Mediterranean Fever. shows the relative positions of D16S84 and hemoglobin α on the short arm of chromosome 16. In male meioses, the recombination rate for these two markers is 0.07,27 28 29 30 corresponding to a map distance of about 7 cM. Using multipoint linkage analysis, we calculated lod scores for various points centromeric to D16S84, between D16S84 and hemoglobin α, and telomeric to hemoglobin α. Figure 2 shows these lod scores plotted against map position. A maximal lod score of 19.86 was observed about 10 cM (on the map of male meiosis) centromeric to D16S84. This represents the most likely map position of the gene causing familial Mediterranean fever, with odds favoring linkage of 1019.86:1 at this point.Homozygosity Mapping
Offspring of consanguineous marriages who have rare recessive diseases should be homozygous for DNA markers near the disease gene,31 because there is a high likelihood that both copies of the gene for a recessive disease, along with the markers on surrounding chromosomal intervals, are derived from a common ancestor. Since our panel of families included several consanguineous couples, we tested for homozygosity at D16S84 and hemoglobin α in affected members of these families. The two uncle—niece marriages are shown in Figure 3Figure 3
Genotypes for 16p Markers in Two Consanguineous Families.. In Family 25, both parents were heterozygous for both markers; the affected son was homozygous for the two markers, whereas the unaffected sons were heterozygous for both. In this example, the chromosome 16 segment containing the gene for familial Mediterranean fever, the A allele of D16S84, and the E allele of hemoglobin α appeared to be inherited as a unit that was probably derived from a common ancestor. Since the affected son would have to have two copies of the disease gene for this recessive disorder to be manifested, he also inherited two copies of the associated alleles of D16S84 and hemoglobin α.In the four offspring in Family 75, homozygosity for the B allele of D16S84 was associated with familial Mediterranean fever. In this family, the disease gene, the B allele of D16S84, and the D allele of hemoglobin α were probably present together on a single ancestral chromosome. Only one of the two affected offspring was homozygous for hemoglobin α; the son bearing the DE genotype represents a recombination between the paternal hemoglobin allele D and the disease-susceptibility gene. This helps define the hemoglobin α complex as the telomeric limit of the gene for familial Mediterranean fever.
As shown in Figure 3, all of the three affected offspring of uncle—niece marriages were homozygous for D16S84, and two of the three were homozygous for hemoglobin α. Our panel also included six first-cousin marriages, which produced 16 affected offspring. For D16S84, only six offspring of these matings were informative, but all six were homozygous. For the highly polymorphic 5'HVR marker, 15 offspring of first-cousin marriages were informative; 12 were homozygous. Therefore, the total number of affected offspring of both types of consanguineous marriages who were homozygous for hemoglobin α was 14 (of the 18 who were informative). Given the same parental hemoglobin alleles in comparable nonconsanguineous families, we would have expected only six homozygous affected offspring. As would be expected, when a single family contained many affected offspring, they were homozygous for the same allele throughout.
Discussion
In this report we present evidence that the gene causing familial Mediterranean fever in non-Ashkenazi Jews is located in the subtelomeric region of the short arm of chromosome 16. We have identified markers in this region that give two-point lod scores far in excess of the level required to demonstrate linkage. Previous analysis of 108 markers on other chromosomes failed to identify any other locus with a two-point lod score meeting this criterion.13 14 15 The multipoint lod score of 19.86 indicates that the odds in favor of the location of the gene for familial Mediterranean fever on chromosome 16 are nearly 1020:1. Moreover, the multipoint data place the gene slightly centromeric to the marker D16S84.
Our data also illustrate the phenomenon of locus homozygosity for inbred offspring with recessive diseases.31 When the highly polymorphic hemoglobin α probe was used, only 4 of 18 affected inbred offspring were not homozygous. Because the gene frequency in our study population is relatively high (about 1 in 22), one or more of the heterozygous affected offspring may have inherited one disease-susceptibility gene (and a linked hemoglobin allele) from one of the persons who married into the inbred family. When the gene frequency is somewhat lower, it should be possible to use homozygosity testing as a primary strategy for mapping recessive disease genes in inbred children, as suggested by Lander and Botstein.31
Identification of the chromosomal location of the gene for familial Mediterranean fever should allow substantial advances in our understanding of the genetic epidemiology of this disease. Although there is at least one documented case of familial Mediterranean fever in the child of a Jewish—Armenian marriage,32 there remains some question whether clinical differences among affected ethnic groups reflect independent genetic loci in these populations. It should be possible to resolve this issue with the information we have at hand. Moreover, we may be able to gain some further understanding of the rare instances in which an illness resembling familial Mediterranean fever appears to occur in populations usually unaffected.33 It will also be of interest to study families with phenotype II disease (amyloidosis preceding acute attacks of familial Mediterranean fever)1 and the few families with an apparently dominant mode of inheritance.34
Of course, the ultimate goal of these studies is the identification of the disease gene itself. In view of the profound clinical manifestations of attacks, it is likely that the gene product plays a major part in inflammation. Although obligate heterozygotes for the gene are phenotypically normal, the high frequency of carriers in affected populations raises the possibility that the gene for familial Mediterranean fever confers a selective advantage on heterozygotes, most likely resistance to an endemic pathogen. Alternatively, a high frequency of carriers of a recessive disease could be due to a founder effect,35 in which a substantial proportion of the affected population is descended from a disease carrier. When such a founder effect exists, one allele of an associated marker locus may be more commonly found in carriers than in the general population (the phenomenon of linkage disequilibrium). We did not observe such an association between the gene for familial Mediterranean fever and specific alleles of either marker locus described here, but we now have preliminary evidence of such an association with other chromosome 16 markers.
Other genes that map to the same region of distal chromosome 16p include the genes for phosphodiesterase IB (PDE1B),36 hydroxyacylglutathione hydrolase (HAGH; also known as glyoxalase II),37 and phosphoglycolate phosphatase (PGP)37 and the gene causing adult polycystic kidney disease (PKD1).38 , 39 None of these genes bear any obvious pathophysiologic relation to familial Mediterranean fever. However, in a somewhat more centromeric location ( 16p 13.1–p11 ) there is a cluster of genes encoding the α subunits of three leukocyte cell-surface-adhesion receptors (integrins): lymphocyte function—associated antigen type I (LFA1A, CD11A), leukocyte surface antigen p150,95 (CD11C), and complement receptor type 3 (CR3A, MAC1A, CD11B).40 Since all three of these molecules are crucial to leukocyte adhesion and cell—cell interactions, it is intriguing to speculate whether this disease may involve another, as yet undiscovered member of the family of chromosome 16 integrins. Alternatively, since the interleukin-4 receptor (IL4R) also maps to this more centromeric area41 and is itself a prototype for a receptor superfamily,42 it is possible that familial Mediterranean fever is a disorder of another cytokine receptor. In any case, the use of positional cloning ("reverse genetics") provides an opportunity to use our new knowledge of the chromosomal location to identify the gene for familial Mediterranean fever itself. This should yield important new insights into the mechanisms of inflammation, and will eventually make possible a laboratory test for this frequently overlooked diagnosis.
Computing time and staff support at the Advanced Scientific Computing Laboratory of the Frederick Cancer Research and Development Center were provided by the National Cancer Institute.
We are indebted to Dr. Igal Kedar for his help and encouragement in organizing this project, to Mr. Mark Ramsburg for technical assistance, and to Ms. Krista Hampsch for help with data management.
Source Information
From the Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md. (E.P., I.A., J.E.B., L.P., A.D.S., D.L.K.); the Department of Medicine F (L.G.) and the Heller Institute for Medical Research (M.P.), Sheba Medical Center, Tel-Hashomer, Israel; and the Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Md. (M.D.). Address reprint requests to Dr. Kastner at the National Institutes of Health, Bldg. 6, Rm. 112, Bethesda, MD 20892.
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