Am JHum Genet 29:523-536, 1977

Recombination, Mutation, or Constitutive Expression at a Gm Locus and Familial Hypergammaglobulinemia G. LEFRANC,1.2 L. RIVAT,3'4 J. P. SALIER,3'4 E. VAN LOGHEM,5 H. AYDENIAN,6 P. ZALZAL,6 L. CHAKHACHIRO,7 J. LOISELET,1 AND C. ROPARTZ8 INTRODUCTION The heavy chains of the IgA2, IgG 1, IgG2, and IgG3 molecules carry antigenic determinants called Am and Gm allotypes. These genetic markers are inherited in fixed combinations characteristic of populations [1-10]. The linkage groups of the respective alleles have been called haplotypes. The sequence of the y genes would be Y2' Y3, and yi as previously assumed [11, 12], but it is not yet known to which side of this 'y-cistron map the a2-cistron is located [7, 8]. It is likely that the great variety of haplotypes described in population data is a result of either mutation or crossing over during evolution; these new genetic events are presumed rare, since they have never been observed in family studies. We report the inheritance of an uncommon haplotype with an unexpected yj allele by a single child in a large kindred. This family will perhaps be informative for the linkage relationship between the three y-cistrons and the a2-cistron and the localization of the latter. Quantitative abnormalities of the IgG subclasses were also noted. SUBJECTS AND METHODS

Sera from a hypercholesterolemic family (family C) were provided by the "Hotel-Dieu" hospital of Beirut. The father and the mother were 1- % cousins (fig. 1); their 10 children ranged in age from 4 to 22. The serum lipid levels were determined according to standard techniques. All sera were tested and quantitated for Glm (1, 3, and 17) and G3m (5, 6, 10, 11, 13, 21, and Received May 26, 1976; revised February 7, 1977. This work was supported in part by the Conseil National de la Recherche Scientifique Libanais, the Fondation pour la Recherche Medicale Frangaise and the University of Rouen. 1 Faculte Francaise de Medecine et de Pharmacie, B.P. 5076, Beyrouth, Liban. 2 Present address: Facultes de Pharmacie et de Medecine Dentaire, Monastir, Tunisie. 3 Unit6 de Recherche, U-78 de l'INSERM sur la Gen6tique des Proteines Humaines, 543, chemin de la Breteque, 76230 Bois-Guillaume, France. 4 Present address: University of Rouen, 76130 Mont Saint Aignant, France. 5 Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands. ff Hopital "Hotel-Dieu," Beyrouth, Liban. 7 Conseil National de la Recherche Scientifique Libanais, Beyrouth, Liban. 8 International Reference Center (WHO) for Human Immunoglobulin Genetic Markers, Centre Regional de Transfusion Sanguine, B.P.5, 76230 Bois-Guillaume, France. © 1977 by the American Society of Human Genetics. All rights reserved.

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24) allotypes; for isoallotype N Glm(l) [formerly non a]; and for the subclasses IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2 by a hemagglutination inhibition system on slides [13, 14] using red blood cells coated with either incomplete Rh antisera or myeloma proteins coupled by the chromic chloride method [15]. The Gm allotype quantitation was performed three times. All sera were also tested (but not quantitated) for the Glm(2), G2m(23), G3m(14), A2m(1 and 2), and Km [formerly Inv] (1, 2, and 3) allotypes. The specific antisera are presented in table 1 together with the locations of the antigenic determinants on the different C'y and Ca homologous regions. The antisera and the method of TABLE 1 REAGENTS USED TO TEST AND QUANTITATE ALLOTYPES, ISOALLOTYPES, AND SUBCLASSES: LOCATION OF ANTIGENIC DETERMINANTS ON DIFFERENT Cy AND Ca REGIONS NOMENCLATURE*

HOMOLOGOUS

SUBCLASSES

Alphameric

Numeric

Allotypes Heavy chains: IgG I ............

Glm(a) (x)

(f) (Z)

IgG2 IgG3

............

............

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(bl) (b3) (b4) (b5) (c3) (c5) IgA2

.............

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(g) A2m(l)

REGIONS

COATING

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276

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NOTE.-Isoallotype Na(NI) on IgGI, IgG2, and IgG3 was tested using antiserum L296 and coating 3. * Nomenclature from WHO workshop, Rouen July 1974. The numeric notation is used in the text. t Anti-allotypes used on slides and on autoanalyzer. t Anti-allotype used on autoanalyzer only; donated by Dr. M. Blanc, Toulouse, France. § Donated by Dr. D. Brazier, London, England. 11 Donated by Dr. B. Zegers, Ultrecht, The Netherlands. # Donated by Dr. J. Shuster, Montreal, Canada. ** Donated by Dr. A. C. Wang, Charleston, West Virginia, U.S.A.

276

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526

LEFRANC ET AL.

quantitation have been previously described [16- 18]. The quantitative control inhibitions were performed on three pools of 10 normal sera from adult Caucasoids who are phenotypically Gm(3;23;5,10,11,13,14), Gm(3;..;5,10, 11, 13, 14), and Gm(1, 3, 17;..;5, 10, 11, 13, 14, 21) and on 19 normal sera from Lebanese adults: five Gm(3;23;5, 10, 11, 13, 14), five Gm(3;..;5, 10, 11, 13, 14), five Gm(l, 3, 17;..;5, 10, 11, 13, 14, 21), two Gm(l, 17;..;5, 6, 11, 21, 24), and two Gm(1, 3, 17;..;5, 6, 10, 11, 13, 14, 24). The inhibiting titers found for each serum sample from family C were compared with control sera with the same phenotypes since a relationship between Gm antigenic strength, IgG subclass concentrations, and phenotype has been demonstrated [19-26]. Experimental and control titrations were performed simultaneously with the same bleeding of each antiserum. Because of the technical errors, only inhibition titers which differed from the controls by at least three dilutions were considered significant. Another quantitation of Glm(1) and G3m(5 and 21) allotypes was carried out using an autoanalyzer as previously described [27]. The concentrations were expressed with arbitrary units (U/l) and compared with the 95% range (mean + 2 SD) of normal values for heterozygous (Gm' 17;21/Gm3;5 10. 11. 13. 14) and homozygous (Gm"1 1721IGm1 17;21 and Gm3;5 10. 11, 13. 14/ Gm3;5l0. 11,13. 14) Caucasoids [28]. The total IgG and IgG3 quantitation was performed by the single radial immunodiffusion test [29] on the sera of our family and two control pools of 10 normal Caucasoid sera, phenotypically Gm(3;..;5, 10, 11, 13, 14) and Gm(1, 3, 17;. .;5, 10, 11, 13, 14, 21), using specific anti-y and anti-y3 antisera prepared in our laboratory. Electrophoresis and immunoelectrophoresis against total serum, IgG light chain and IgG heavy chain antisera were carried out by routine methods. Sera were also tested for anti-IgG (anti-allotypes, anti-antibodies) with anti-Rh coated red cells. All sera were screened for the presence of anti-nuclear autoantibodies, using erythrocytes coated with desoxyribonucleoprotein and for the presence of rheumatoid factors by the Waaler-Rose test and latex gammaglobulin test.

Nine and 12 months after the initial tests, new blood samples were collected to re-evaluate serum lipids, Gm phenotypes, and IgG levels and to determine ABO, Rh, C, c, D, E, e, M, N, S, s, Mg, Jk , Jkb, Lea, Leb, P red cell antigens, G6PD, ACP, AK, ESD, PGM1, PGM2, red cell enzymes, Hb, Hp, Gc, Alb, Tf, and al-antitrypsin serum proteins according to the standard techniques. Sensitivity to the taste of phenylthiocarbamide (PTC) has also been tested. A blood sample from one of the mother's brothers has been analyzed for most of these genetic markers but mainly for Gm allotype quantitation. RESULTS

All sera were phenotypically Km(3). The Gm and Am typing showed a rare Gm phenotype for one child (V-9). The father (III-1; fig. 1 and table 2) has the phenotype Gm(1, 3, 17;..;5, 10, 11, 13, 14, 21) Am(l).* His probable genotype is Gm 1 17; -;21Am 1/Gm3;.. 5' 10, 11, 13, 4Am 1 since he transmitted Gm ' 17"1;2Am 1 to three of his children (V-2, V-6, and V-7) and the haplotype Gm3;;5 -10. 11.13. 4Am1 to six others (V-1, V-3, V-4, V-5, V-8, and V-10). The mother, IV-1, whose phenotype is Gm(I, 3, 17;..;5, 6, 10, 11, 13, 14, 24)/Am(l, 2) is probably heterozygous (Gm3;"5 10, 11, 13, 14AmIGml17'..;5. 6,11, 24Am2). She transmitted Gm' 17;..;5. 6. 11. U Am2 to three of her children (V-2, V-4, and V-7) and Gm3';5 10. 11. 13, "4Am1 to six others (V-1, V-3, V-5, V-6, V-8, and V-10). The rare phenotype of the proposita * The allotypic markers are written in the numerical order of the subclasses, with semicolons separating the subclasses and commas between the allotypic markers. G2m(23) is the only allotype presently defined on the IgG2 heavy chain; two dots are used to indicate that the sera were tested and found to be negative for

G2m(23).

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data and the inhibition titers are not always in strict agreement. For example, all the IgG3 levels from 1.88 g/l to 4.4 g/l are significantly elevated, but some G3m(5 and 21) allotype quantitative data from the autoanalyzer (fig. 1) and some inhibiting titers (table 3) are within the normal limits. Nevertheless, the concentrations in these sera are near the upper limit of the normal range, and inhibition titers are fourfold higher than normal. For the G3m(5, 10, 11, and 13) allotypes carried on the same polypeptide chain, it is also surprising to find significantly elevated titers for G3m(5 and 13) but not G3m(1O and 11). These apparent inconsistencies could be due to the different affinities of the anti-allotype sera. Moreover, serum lipid elevations noted in this family perhaps affect the text systems. The unexpected presence of IgGI carrying the Glm(3) allotype in the serum of the proposita (V-9) remains to be explained. The hypothesis of paternal exclusion will not be considered further; none of the other genetic markers excludes paternity and some of these (ABO, Rh, ACP, PGM1, taste sensitivity to PTC, and hypercholesterolemia) strengthen the probability of paternity. Thus, the proposita has inherited an uncommon haplotype from one of her parents. This haplotype could be a result of recombination in either parental gamete, unequal crossovers within the linkage group of the y-cistrons, or a transmission of a completely duplicated Cy, gene (fig. 2a). The new haplotypes would be either Gm3; 117;--;21, which has been described [38-41], or Gm3; 1, 17;..;5, 6, 11, 24. A partially duplicated gene coding for one single larger Cy1 chain, may have resulted from a mispairing of C'y, alleles, but this study does not permit the evaluation of the larger chains. Immunoabsorption experiments could give a definite answer. Equal crossover on either side of the Cy>'1 homologous regions (fig. 2b), resulting in Gm1 3; ;21 or Gm1' 3;;5 6, 11, 24, seems extremely unlikely. An equal intercistronic crossover between the C'y1 and C'Y3 cistrons (fig. 2c) appears to be a far more likely explanation, and the proposita might have inherited Gm3;-21 or Gm; ;5 6. 11, 24. Such Gm-gene complexes have been described [41, 42]. It is impossible to choose among all the possible haplotypes that the proposita could have inherited because the uncommon Cy, gene is masked by the GmL 17 allele carried by the other haplotype. Nevertheless, the hypothesis of recombination during maternal meiosis is particularly interesting for studying the linkage relationship between the y-cistrons and the a2-cistron and the localization of the latter. The heterozygous mother (Am lIAm2) would have transmitted an unexpected C'y> gene linked to the Gm5.6f 11'24 CY3, Gm-23 Cy2, andAm2 Ca2 alleles. Consequently, the a2-cistron would be located near the N-terminal side of the y-cistron linkage group and the sequence of genes would be a2, 74, 72, Y3, and yi (fig. 2). A point mutation is also a possibility. The Gm3 and Gml7 are homoalleles and code for the Fd or C,'1 homologous region. These two antithetical markers are related to a single amino acid interchange; Glm(3) is associated with Arg and Glm(17) with Lys at residue 214 of the heavy chain. A single base change can change G1m(17) (codons AAA and AAG) to Glm(3) (codons AGA and AGG). Accordingly, the probable genotype of the proposita (V-9) would be Gm' 17;--;21 Am /Gml. 3;..;5, 6, 1l, 24Am2 or Gm1' 3X;21 Am1/Gm" 17,.;-5, 6, 11, 24Am2. The Gm 1 3;..;21 has been reported [43]. If Gm" 3;..;5. 6. 11, 24 really existed, it would possess a Mongoloid Cy1 gene linked to a Negroid C'3 cistron.

532

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There is an alternative explanation for the uncommon presence of the Glm(3) allotype. The large numbers of genes from the IgV region [44-49] and to a smaller degree, of IgC cistrons [50-52] have probably evolved through gene duplication from a common ancestral gene. Cy cistrons may be more numerous than has previously been assumed. Probably, a control at a level equivalent to regulatory genes determines which fraction of the immunoglobulin structural genes is expressed in each mature plasma cell. Rivat et al. [53, 54] have demonstrated the in vitro synthesis, by lymphocyte culture, of IgG positive for certain Gm allotypes from individuals phenotypically negative for these markers. Comparable qualitative changes of expressed allotypes have been observed in cell culture of two mouse plasmacytomas [55], in transplanted lymphoid cells [56], in inbred mice [57], in hyperimmune rabbits [58], and in mouse tumor cell lines (in the H-2 system; [59, 60D. All of these reports of nonallelic behavior of allotypes suggest that a constitutive expression or derepression might be a more general phenomenon [61] which is consistent with the hypothesis that a full set of structural genes for all allotypes would be present in each individual [62]. The control of gene expression would usually be quite stable. The unexpected

LINKAGE AT THE Gm LOCUS

533

derepression of a normally repressed or silent gene could arise by uncommon cellular response to environmental, metabolic, pathological, or experimental perturbations of a regulatory mechanism. The genotype of the female, V-9, thus would be Gm', 17,;..;2lAm1Gm.117;.;5, 6, ,24Am2 + Gm3 or Gm', 17; -;21 Am' + Gm3IGm1, 17;..;5, 6, 11, 24Am2.

SUMMARY

In a hypercholesterolemic Lebanese family, an uncommon Gm haplotype carrying an unexpected Cy1 gene was inherited by only one of 10 siblings. A new recombination during the maternal or paternal meiosis could explain its formation. According to this hypothesis, our data would be informative for the linkage relationship between the y-cistrons and the a2-cistron. The latter might be located near the N-terminal side of the y-cistron linkage group, and the sequence of genes would be a2, y4, Y2, y3, and yl. A mutation could also effect the change from Glm(17) (codons AAA and AAG) to Glm(3) (codons AGA and AGG). Another alternative is to postulate a constitutive expression of a Cy1 structural gene which, normally, would not be expressed. The uncommon derepression could be the consequence of uncommon cellular response to environmental, pathological or metabolic perturbation of a regulatory mechanism. ACKNOWLEDGMENTS We wish to thank Mr. G. Merhege and Mr. G. Hagopian for their collaboration which was greatly appreciated; Mrs. M. Dutheil, Mrs. M. Gremont, Mrs. M. T. Schouft, Mrs. M. Botter-van Goch, Miss D. Ozanne, and Miss G. de Lange for skillful technical assistance; Dr. J. P. Martin (U-78, INSERM), Dr. J. Seger (C.N.T.S., Paris); and Miss N. Baki for the typing of some genetic markers. We would also like to thank Drs. M. Blanc, D. Brazier, J. Schuster, A. C. Wang, and B. Zegers for providing us with valuable reagents. The authors are indebted to Dr. A. G. Steinberg for helping with the manuscript.

REFERENCES 1. NATVIG JB, KUNKEL HG: Genetic markers of human immunoglobulins: the Gm and Inv systems. Ser Haematol 1:66- 96, 1968 2. STEINBERG AG: Globulin polymorphisms in man. Annu Rev Genet 3:25-52, 1969 3. GRUBB R: The genetic markers of human immunoglobulins, in Molecular Biology, Biochemistry and Biophysics, no. 9. Berlin, Springer-Verlag, 1970 4. STEINBERG AG: Contribution of the Gm and Inv allotypes to the characterization of human populations. Isr J Med Sci 9:1249- 1256, 1973 5. VYAS GN, FUDENBERG HH: Am(1), the first genetic marker of human immunoglobulin A. Proc Natl Acad Sci USA 64:1211- 1216, 1969 6. KUNKEL HG, SMITH WK, JOSLIN FG, NATVIG JB, LITWIN SD: Genetic marker of the A2 subgroup of yA immunoglobulins. Nature 223:1247-1248, 1969 7. VAN LOGHEM E, NATVIG JB, MATSUMOTO H: Genetic markers of immunoglobulins in Japanese families. Inheritance of associated markers belonging to one IgA and three IgG subclasses. Ann Hum Genet 33:351- 359, 1970 8. VAN LOGHEM D, WANG AC, SHUSTER J: A new genetic marker of human immunoglobulins determined by an allele at the a2 locus. Vox Sang 24:481-488, 1973

534 LEFRANC ET AL.

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9. LEFRANc G, LoiSELET RiVAT L, ROPARTZ C: Gm, Ki, and 1Sf allotypes in the Lebanese population. Acta Anthropogenetica 1:34-45, 1976 10. LEFRANc G, RIVAT L, SERRE JL, LALOUEL JM, PISON G, LoiSELET ROPARTZ C: Further studies about immunoglobulin allotypes among Lebanese communities. In preparation 11. KUNKEL HG, NATVIG JB, JOSLIN FG: "Lepore" type of hybrid y globulin. Proc Nati Acad Sci USA 62:144-149, 1969 12. NATVIG JB, KUNKEL HG: A hybrid IgG4-IgG2 immunoglobulin. J Immunol 112:12771284, 1974 13. ROPARTZ C, RiVAT L: Determination des groupes Gm, Inv et 1Sf. Detection des des anti-Rh. Immunology Techniques. Unit of Immunology antiglobulines. WHO, vol 32, 1967 la 14. RIVAT L, BURTIN , d'un C: Mise en dites acquises. de certaines sous-cJasses de yG dans des synthese Humangenetik 8:183-194, 1969 15. GOLD ER, FUDENBERG HH: Chromic chloride. A coupling reagent for passive nation. J Immunol 99:859-866, 1967 C: Evidence for "deleted" or 16. J, G, L, C, constant for the region of the y3 chain. Am at the locus coding ozygous genes "silent" JHum Genet 28:51-61, 1976 17. RIVAT L, DAVEAU M, C: Les IgG dans les aberrations chromosomiques: Gm et de certaines familiale de quantitative des allotypes du sous-classes Humangenetik 24:173-190, 1974 18. RIVAT L, C, DAVEAU M, ROPARTZ C: Comparative frequencies of anti-IgA antibodies among patients with anaphylactic transfusion reactions and among normal blood donors. Clin Immunol Immunopaihol 7:340-348, 1977 19. LITWIN SD: A quantitative method for determining human yG allotype antigens (Gm). Relationship between Gm antigenic strength and phenotype. J Immunol 106:589-597, 1971 20. YOUNT WJ, KUNKEL HG, LITWIN SD: Studies of the Vi (y2c) subgroup of y-globulin. A between concentration and genetic type among normal individuals. J Exp Med relationship 125:177- 190, 1967 E, TERRY WD: Correlations 21. MORELL A, SKVARIL F, STEINBERG AG, VAN between the concentrations of the four subclasses of IgG and Gm allotypes in normal human sera. JImmunol 108:195-206, 1972 E: The effect of Gm(23) on the 22. STEINBERG AG, MORELL A, SKVARIL F, VAN 1642-1645, 1973 concentration of IgG2 and IgG4 in normal human serum. J Immunol E: Qualitative and 23. VAN DER GIESSEN M, FREYEE W, Rossouw E, VAN an antiserum capable quantitative studies on IgG2 globulins in individual human sera withImmunol 14:127-139, of differentiating between Gm(n +) and Gm(n -) proteins. Clin Exp 1973 24. LITWIN SD, BALABAN A quantitative method for determining human yG allotype antigens (Gm). Differences in Gm gene expression for yG I and yG3 H-chains in sera. J Immunol 108:991-999, 1972 25. LITWIN SD: A quantitative method for determining human yG allotype antigens (Gm). Gm genes and gene complexes in different human populations. Clin Genet 3:206-213, 1972 26. SHAKIB F, STANWORTH DR, DREW R, CATTY D: A quantitative study of the distribution of IgG subclasses in a group of normal human sera. J Immunol Methods 8:17-28, 1975 27. SALIER JP, RIVAT L, CARTRON JP, ROPARTZ C: Quantitative studies of Gm allotypes. I 1976 Reappraisal of the method using an autoanalyzer. J Immunol Methods 28. RIVAT L, SALIER JP, NORTH MD, ROPARTZ C: Quantitative studies of Gm allotypes. G l), G3m(5) and G3m(2 1) in sera from Caucasoid healthy blood donors and in a family haplotype. J Immunol. In with the inheritance of a gene responsible for a weak Gm press, 1977

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