No. 4] An A2B3 Phenotype Blood Showing Atypical Mode of Inheritance 317

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1 316 [Vol. 41,, 72. An A2 B3 Phenotype Blood Showing Atypical Mode o f Inheritance By Hideo YAMAGUCHI, Yasuto OKUBO, and Fumio HAZAMA Osaka Red Cross Hospital and Osaka Red Cross Blood Center (Comm. by Taku KOMAI, M.J.A., April 12, 1965) The propositus is a 10-year-old healthy Japanese girl whose blood. was easily typed as of AB group with anti-b antibody in her serum... Further detailed examination indicated that both the antigens A and. B in her cells were weaker than those of normal AB group, while in her saliva she secreted A- and H-substances, but no B-substance. The pedigree studies revealed that there were four individuals of

2 No. 4] An A2B3 Phenotype Blood Showing Atypical Mode of Inheritance 317 similar atypical weak AB group in her family (Figure) who were divided into two groups, namely, the propositus (III-1) and one grandf ather(i-3) had both weak A and B antigens, while the other two, her sister(iii-2) and mother(ii-2), had normal A, antigen and much weaker B antigen than that in the propositus' cells. All these individuals had anti-b antibody in their sera and secreted A- and H-substances in their saliva. Serological Findings. Red cells: The agglutinability of the red cells of these four atypical AB members is shown in the Table., All of them gave strong positive reaction with anti-a reagents, but the cells of III-1 and I-3 failed to react with Dolichos bi f lorus extract (plant anti-a1 agglutinin) and with 3 human anti-a1 sera, showing that their A antigen may belong to the A2 phenotypic level. The absorption-elution test of these cells with Dolichos bif lorus extract revealed that the eluates from these cells did not contain anti-a1.. The cells of III-2 and II-2 showed distinct reaction with the anti-a1 lection. Ulex europaeus extract agglutinated all the four individuals cells. Table. The Agglutinability of the Red Cells The red cells of the propositus and of I-3 gave slightly stronger reactions with anti-b sera tested(several diagnostic reagents and more than ten random-selected group-a human sera) than did those of III-2 and II-2. The diagnostic reagent anti-a(ortho) (titre 1:256) gave titres of 1: against all the red cells of the four individuals, while: the anti-b(ortho) of the same titre reacted only with the cells at the very low titre of 1: 8(III-2 and II-2) or 1: 32(III-1 and I-3). The cells of these four individuals began to agglutinate almost. as rapidly as did the normal AB group cells against anti-a reagent (1: 256). On the other hand, to anti-b reagent(1: 256), it took more than ten seconds to agglutinate for the cells of III-1 or of I-3, and more than one minute for those of III-2 or of II-2. There were striking differences in the avidity of these cells to anti-b reagents, which agglutinate normal A1B cells within 10 seconds.

3 318 H. YAMAGUCxi, Y. OKUBO, and F. HAZAMA [Vol. 41, As was to be expected, the cells of III-1 and I-3 absorbed anti-a in a relatively smaller amount than did those of III-2 and II-2 which absorbed anti-a to nearly the same extent as did the cells of the normal A1B control. The ability of the cells in these individuals to absorb anti-b was much smaller than that of the normal A1B cells. The eluates of these cells, however, showed a specific anti-b antibody, which was reconfirmed by inhibition test using B-substance. Serum: The propositus' serum contained anti-b antibody of a low titre, namely, her serum reacted positively with 21 AB- and 13 B-cell specimens, but failed to agglutinate and 10 A-cell specimens, randomly selected. The activity of the serum to agglutinate B cells was specifically inhibited by the same volume of B- substance, but not by A-substance. The sera of the remaining three individuals also contained a similar anti-b antibody of varying titres. We could not detect in these sera any other atypical antibody such as anti-a1, anti-lea or anti-p,. The anti-b antibodies in the sera of these four individuals failed to react with the atypical AB cells possessed by the members of the same family. The atypical AB cells of the four members were tested to see if they had not been subjected to auto-sensitization with their own anti-b, by means of the direct Coombs' test and the elution test, but without any positive evidence for such. A normal human anti-b, which had been absorbed by the cells of III- 1 to the extent that the serum could no longer agglutinate the cells of III-1, was still active to the normal B or AB cells. The anti-b sera of these four persons, even though low in titre (1:1--8), remained active even at 37 C. Saliva: All members of the four atypical AB group of this family secreted as much A- and H-substances in their saliva as did the normal AB group person. But surprisingly, some of the saliva lacked in B-substance and some contained only a trace of that substance. From the above serological findings, the B factor of these four individuals seems to belong to the third type of weak B (Race and Sanger, 1962) (1) in which H-substance is present but lacking in (or doubtful) B-substance in saliva, even though the anti-b in serum was detectable in our cases. We accordingly, following Sussman et al. (1960) (2), propose to designate this weak B as B3 provisionally. This symbol, however, does not seem to be quite appropriate because of the presence of remarkable antigenic differences as to the B factor among the four atypical AB groups. At any rate, the phenotypes of our four weak AB group are to be designated as:-propositus (III-1): A2B3f III-2: A,B3i II-2: A1B3f

4 No. 4] An A2B3 Phenotype Blood Showing Atypical Mode of Inheritance 319 and I-3: A2B3. Recently several cases of weak B have been reported (Yamaguchi et al.) (3). However, as far as we know, there is no example of A2B3 except the one reported by Suzuki (1958) (4). Pedigree Studies. The propositus, III-1, of the phenotype A2B3, is the eldest daughter of Al father (II-1) and A1B3 mother (II-2). One of her two sisters, III-2, is of the phenotype A1B3. We accordingly had expected that their father should be A1A,2, and their B3 factor should have been derived from the mother. When we tested the bloods of I-1, I-2, and I-3, however, we found the following difficulties:-the genotype of the f ather(ii-1) could not be A1A2, but should be A10, judging from his parents' bloods(a1 and 0). No such discrepancy was detected as to other blood-group systems (see Figure). Recently we came across with two reports dealing with weak and atypical B antigen by Andersen(1960) (5) and by Seyf rigid et al. (1964) (6). The authors assumed that these families had an A-gene and an atypical B-gene occurring at the same locus on one and the same chromosome. We consider that this idea might fit our family, since one of the grandfather (I-3) of the propositus had the same phenotype as her own. Thus, the propositus may have received A2B3-gene from her mother, and 0-gene from her father, then her genotype should be 0/A2B3. The genotypes of the remaining three members examined seem to be Al/A2B3(III-2, II-2) and 0/A2B3(or A2/A2B3)(I-3). The genotype A,/A2B3 was probably manifested as the phenotype A1B3f because the A2-gene is believed to be recessive to the A,-gene. The observation that the B antigen of the A1B3 in our family is somewhat weaker than that of the A2B3 can perhaps be explained by the hypothesis suggested by Alter and Rosenfield (1964) (7), According to them, in some AB-cases, the B-gene suppresses the expression of the A-gene. If so, we could assume that the antigenic variations of B3 factor among our family members may depend on the A-genes. Acknowledgements:, The authors wish to offer their thanks to Prof. T. Komai for his valuable discussion and help in preparing this manuscript and also to Prof. R. Kimura for his constant encouragement. References 1) Race, R. R., and Sanger, Ruth: Blood Groups in Man. 4th ed. Blackwell Scientific Publications, Oxford (1962). 2) Sussman, L. N., Hannah, P., and Lacher, M. J.: Blood, 16, 1788 (1960). 3) Yamaguchi, H., Okubo, Y., Hazama, F., and Oyama, S.: Proc. Japan Acad., 40, 357 (1964). 4) Suzuki, T.: Hanzaigaku Zasshi, 24, 1 (1958).

5 320 H. YAMAGUCHI, Y. OKUBO, and F. HAZAMA [Vol. 41, 5) Andersen, J.: 6) Seyf ried, H., 7) Alter, A.A., Blood, 16, 1163 (1960). Walewska, I., and Werblinska, B and Rosenfield, R. E.: Blood, 23,.: Vox Sang., 9, 605 (1964). 268 (1964). Appendix:- Note by Taku Komai (M.J.A.): The present paper by Dr. Yamaguchii and his associates seems to be of special genetic interest, since it apparently has presented a conclusive evidence for the hypothesis that the genes governing the ABO-blood groups are not allelic in the strict sense, rather, the genes for A and B are pseudo-allelic. Crossing over between the loci A and B may take place onn very rare occasions, and bring the genes for A and B in close juxtaposition onn one and the same chromosome. I-3, II-2, III-1, and III-2 in the pedigree seem to carry such a chromosome. The observation that the B antigen in these individuals (designated as B3) showed strikingly weaker agglutination than did the normal. B antigen is apparently due to a position effect-the B gene gives a weaker effect in cis-arrangement with A(AB/O) than in trans-arrangement (A/B). The authors' observation that the Ba antigen showed a somewhat weaker activity in combination with Al than with A2, may be due to the fact that the Al individuals in the family, II-2 and III-2, carry both A1 and A2 genes, whereas the A2 individuals,. I-3 and III-1, have only A2 gene beside 0. The multiple allelism of the ABO-group genes had been taken as grantedd for more than thirty years by practically all blood-type specialists and the majority of human geneticists. However, there have been doubts current among some animal and general geneticists especially of the British school. I suggested a similar view in my paper published in 1950 ("Semi-allelic genes". Am. Nat., 84, ).