Brief Reports

Vox Sang. 17: 5-10 (1969)

Abnormalities in Synthesis of some Subclasses of yG in a Family with Two Cases of Ataxia Telangiectasia

LILIANE RIVAT, C. ROPARTZ, P. BURTIN and D. KARITZKY

Centre Ddpartemental de Transfusion Sanguine, Bois-Guillaume; Institut de Recherches Scientifiques sur le Cancer, CNRS, Villejuif,

and Universitats-Kinderklinik, Freiburg i. Br.

The first work concerned with the investigation of certain Gm and Inv factors in agammaglobulinaemia families was that of FUDENBERG et al. [4].

From the location of factors in these systems, carried by the heavy chains of the three, yG, y A and yM types of immunoglobulins, respectively, they presented a tentative schema of the genetic me- chanism which governs the synthesis of immunoglobulins.

Since then, the yG heavy chains have been further divided into four types: yG,, yG,, yG, and yG, [5, 121.

Studies of each of these chain subtypes made it possible t o locate accurately the factors of the Gm system. Thus, the Gm ((1,2, 4,8, 9, 17,18 and 22)) factors were found to be on the yG,, the Gm (8 and 23) on the yG, and the Gm ((5,6,10,11,13,14,15,16 and21)) factors on the heavy chains of the yG, type.

In a family where two children are suffering from ataxia telangiec- tasia together with a major deficiency in yA, we have been able, by determination of the Gm phenotypes in the apparently healthy father, whose yG level was normal, t o demonstrate a deficiency in yG, molecules, Gm(1, 17) and in one affected child a deficiency involving the yG, molecules.

The yG, y A and yM immunoglobulins were determined in the serum of every member of the F. family (table I) by the radial diffusion technique.

While the parents, as well as children B. and D., have normal immunoglobulins and are clinically healthy, two sons, W. and G.,

6 RIVAT et al. Abnormalities in Synthesis of some Subclasses

Table I . Concentration (mg%) of yG, yA and yM in the serum of the members of the F. family

YG 7-4 Y M

Father 1060 238 81 Mother 1400 132 93 B . . . 1350 172 70 D... 920 148 49 W. . . 450 0 272 G . . . 550 0 245

who have a total deficiency in yA, decreased yG and increased yM, are suffering from ataxia telangiectasia.

The Gm((1, 2, 4, 5, 8, 10, 11, 17 and 21)) and the Inv(1 and 2) factors were determined by the classical inhibition method on slide [9].

The amount of available serum did not allow us to isolate the yG. The inhibiting power of each sample is therefore expressed not by the mg/ml protein concentration of the last dilution inhibiting the reaction, but by the titre of the serum which has this effect.

The inhibitions obtained for the Gm((4, 5,10, 11 and 21)) factors with each of the positive sera are similar to those of a normal control serum, and reach 1/64 for the Gm(4) and Gm(21), 1/256 for the Gm(5), Gm(l0) and Gm(l1) factors.

We find that the inhibiting titre of Mr. F.’s serum against the anti- Gm(1) and the anti-Gm(l7) antibodies is 64 times smaller than that of a normal serum Gm(1, 17).

Indeed, inhibition is not more than 1/8 whereas the titre reached by the control serum equals 1/512 (table 11).

While the Gm(8) factor in both parents’ and three children’s serum inhibits the agglutinating complex a t 1/32 and 1/64, the inhibiting power of W. is not more than 1/4 (table 111).

The Gm and Inv phenotypes of all members of the family are shown in table IV.

The immunological abnormalities of the children with ataxia telangiectasia, though not consistent, are known [3, 6, 7, 11, 131, as well as the deficiency involving the y A of the clinically healthy parents of several subjects similarly affected [2].

The weakened expression of certain Gm factors suggests that in two members of this family a deficiency may exist which involves one type of yG molecules.

Table 11. Inhibitions obtained with the F. serum against the anti-Gm(1)'and anti-Gm(l7) antibodies

Gin( 1) Gm( 17) 114 l/8 1/16 1/32 1/64 1/128 1/256 1/512 1/10241/4 1/8 1/16 1/32 1/64 1/128 1/256 1/512 1/1024

Mr. F. 0 0 1 2 2 2 2 2 2 0 0 1 2 2 2 2 2 2

C o n t r o l : + O 0 0 0 0 0 0 0.5 1 0 0 0 0 0 0 0 0 1

C o n t r o l : - . 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

Notation uf results:

No agglutination: 0

Agglutination: 1 or 2 according to strength of agglutination.

m 0 cc

8 RIVAT et al. Abnormalities in Synthesis of some Subclasses

Table ZZI. Inhibiting power of each of the F. family’s sera against the anti-Gm(8) complex

Factors G 4 8 ) Dilutions Sera 112 114 118 1/16 1/32 1/64

Father 0 0 0 0 0.5 1 Mother 0 0 0 0 0 0.5 D.. . 0 0 0 0 0.5 1 B. . . 0 0 0 0 0 1 G... 0 0 0 0 0.5 2 W.. . 0 0.5 1 2 2 2

Table ZV. Gm and Inv phenotypes of members of the F. family

Gm (1, 2, 4, 5, 8, 10, 11, 17, 21) Inv (1, 2)

Father $ 1 - + 4- + + + + 1 + - - Mother - - + + + + + - - - - D.. . - - + + + + + - - - - B . . . - - + + + + + - - - - G.. . W . . . - - + + + + + - - - -

- - + + + 1 + + - - - -

The inhibition obtained is weaker than that of control serum. -

The father, clinically healthy, whose yG were quantitatively nor- mal, has the Gm(1, -2, 4, 5, 8, 10, 11, 17, 21) phenotype.

Among all factors present, only those carried by a definite type of molecule, Gm(1) and Gm(17) have a weakened expression. One of these factors is carried by the Fc fragment, the other by the Fd fragment of the molecule of the yG, type. Simultaneous decrease of the inhibiting power of the two antigens supports the hypothesis expressed. The deficiency involving the yG, type chains is not total since the Gm(4) factor is expressed normally.

The probable genotype of this subject is Gml. 179 21/Gm49 5 , 8,10* 11

whereas the mother’s is Gm4. 5 , 8 9 10, 11/Gm49 6, 81 10, 11.

None of the children is phenotypically Gm(1, 17, 21). Both sons with ataxia telangiectasia have a total deficiency in yA, but also a significant deficiency in yG.

of yG in a Family with Two Cases of Ataxia Telangiectasia 9

It is quite possible t o accept that they received the Gml. 173 z1 gene from the father, a pathological gene since it results in the abnormal synthesis of one type of molecule.

This gene would remain ‘silent’, or it would result in synthesis of proteins being too weak to be possibly demonstrated by the presence of the Gm factors.

In W., the expression of the Gm(8) factor is almost nil. This antigen is located on the Fc fragment of the molecules of the yG, type [lo]. The quantitatively normal presence of the Gm(4) factor in this subject leads us to believe that the deficiency involves solely the yG, chains.

Such quantitative abnormalities of the expression of some factors of the Gm system are to be compared with what has been observed in families where one member is affected with ‘atypical hypogamma- globulinaemia’ [8].

While in Caucasians the Gm((4, 5 , 8, 10 and 11)) factors are in- herited as a whole i t is necessary in these families t o postulate the possible existence of very rare genes, such as the Gm4> Gm’. 4,

Gml. 4 9 genes, if we wish to understand the phenotype abnormalities observed. These abnormalities are found not only in subjects with hypogammaglobulinaemia but also in other members of the family who present no immunological disorder.

The abnormality in the synthesis of an immunoglobulin is asso- ciated with a genetical disorder, often involving all the gamma- globulins and inherited by certain members of the family.

Studies by BURTIN et al. on families with atypical agamma- globulinaemia [ l ] show that when one member exhibits a deficiency involving a large class of immunoglobulin, a slight abnormality of another class of immunoglobulin can be observed in one or several other subjects.

In the F. family the disarrangement of the yG in the father may have entailed the immunological troubles observed in two children. It is indeed likely that interactions exist between the several synthesis and that disturbance in one mechanism results in upsetting the other regulation systems.

Studies of various factors of the Gm system thus allowed us t o demonstrate a deficiency in yG, which determination by an anti-yG had failed to reveal, or had not indicated precisely. Moreover, they enabled us t o decide t o which chain-subtype the abnormality be- longed.

Gml. 2 $

10 RIVAT et al.

Systematic determination of these factors in all the families where one member shows an immunological disorder of any type should provide the means of approaching and enlightening the problem of immunoglobulin synthesis.

References

I . BURTIN, P.; BUFFE, D. et GRABAR, P.: Les hypogammaglobulinBmies aty- piques. Ann. I n s . Pasteur, T. 106 (1964).

2. EPSTEIN, W. M. L.; FUDENBERG, H. H.; REED, W. B.; BODER, E. and SED- GWICK, R. P. : Immunologic studies in ataxia telangiectasia. Int. Arch. Allergy 30: 15-29 (1966).

3. FIREMAN, P.; BOESMAN. M. and GITLIN, D.: Ataxia telangiectasia, dysgamma- globulinemiit with deficient gamma 1 A globulin. Lancet i: 1193 (1964).

4. FUDENBERG, H. H.; HEREMANS, J. F. and FRANKLIN, E. C.: A hypothesis of the genetic control of the gamma-globulins. Ann. Inst. Pasteur 104: 155 (1963).

5. GREY, H. M. and KUNKEL, H. G.: H. Chain subgroups of myeloma proteins and normal 7 S gammaglobulins. J. exp. Med. 00: 120-253 (1964).

6. LEVEQUE, B.; DEBAUCHEZ, CL.; DESBOIS, J. C.; FEINGOLD, J.; BARBET, J. et MARIE, J. : Les anomalies immunologiques et lymphocytaires dans le syndrome d'ataxie telangiectasie. Ann. PCdiat., Paris 1 1 : 717 (1966).

7. PETERSON, R. D. A.; KELLY, W. D. and GOOD, R. A.: Ataxia telangiectasia, its association with defective thymus immunological defiriency disease and malignancy. Lancet i: 1184 (1964).

8. RIVAT, L.: SystBmes Gm, Inv, ISf et Immunoglobulinopathi~s, Tlibse de mklecinc, Rouen (1967).

9. ROPARTZ, C. et RIVAT, L.: DBtermination des groupes Gm, Inv et ISf. DCtection des antiglobulincs. SpBcificitB des anti-Rh. Immunology techniques. Unit. of Immunology WHO, Sept. 1967.

10. ROPARTZ, C.; RIVAT, L. e t RIVAT, C.: Relations entre les allotypes et la structure immunologique des ch ines lourdes des yG humaines. XI. International Con- gress of Microbiological Standardization, Milan, Sept. 1968.

11. ROSENTHAL, I. M.; MARKOWITZ, A. S. and MEDENIS, R.: Immunologic in- competence in ataxia-telangiertasis. Amer. J. Dis. Child. 110: 69-75 (1965).

12. TERRY, W. D. and FAHEY, J. L.: Subclasses of Human yz globulin based on differences in the heavy polypeptide chains. Science 146: 400 (1964).

13. YOUNG, R. R.; AUSTEN, K. F. and MOSER, H. W.: Abnormalities of serum ylA gloldin and ataxia-telangiectasia. Medicine 43: 423 (1964).

Authors' addresses: Dr. LILIANE RIVAT, Groupe de Recherche de 1'I.N.S.E.R.M. lJ 78 sur la GBnttique des ProtBines Humaines, F-76 Bois-Guillaume (France); Dr. C. ROPARTZ, Centre DCparteniental de Transfusion Sanguine et de Gdnktique Humaine, F-76 Bois-Guillaurne (France); Dr. P. BURTIN, Institut de Recherches Scientifiques sur le Cancer, Centre National de la Recherche Scientifique, F-94 VilEejudf(France); Dr. D. K ~ ~ 1 ~ z ~ ~ , U n i v e r s i t a t ~ - K i n d e r k ~ i n i k , ~ - 7 8 U U F r e i b u r ~ i.Br. (Germany).