4')2 COKUADO HA(.I.I()X1 



tlu' ;n-ailal)l(' a-., diinci".^. Aggregation of identical dinici's may in this case 

 result in the formation of abnormal hemoglobin molecules, like ilh-H 

 (^/) and Ill)-Bart's (y,^') (soc Section TV. 111. in /? chain thalassemia 

 there is a deficit in the /? chain production; in the heterozygote f3-^/ft'^^\ 

 for instanci', oidy the /f^ gene is ()|)erating and the i-ate of synthesis of 

 f3 chains is lowered to approximately lialf the normal \'alue. Since the 

 rate of synthesis of 8 chains is not affected by the presence of a thalas- 

 semic gene, the relative amount of Ilb-A:.. appeal's to be rloubled over 

 normal values. In sickle-ccll/thalassemia anrl in other combinations of 

 a thalassemic gene with one of the (S alleles, such as /3^, f3^, or (3^, the 

 rate of pi'oduction of /)"'. f3^\ or /3" chains, resl^ecti^•ely. is liigher tlian 

 that of the /3 chains i)roduced under the control of the jff''"'' gene. fS chain 

 thalassemia is thus of an increased Hb-A^ type and interacts with ft 

 alleles. 



The denomination thalassemia includes a group of hei'editary anemias 

 heterogeneous fi'om a genetic point of view; thalass(>mia minor may be 

 caused by heterozygosity for several possible a"^'' oi- /?''''' pseudoalleles 

 and thalassemia major by homozygosity for two a^^' or /?''"'' genes or pos- 

 sibly by interaction of one a'^^' with one ft'^^ gene. The heterogeneity of 

 thalassemia is in accordance with the variability of the hematological 

 and clinical picture; the possibility exists that different thalassemic genes 

 have different expressivity and penetrance. A form of thalassemia of 

 intermediate severity, whicli had been designated thalassemia inter- 

 media, may possibly result from the combination of thalassemic genes 

 with low expressivity; other factors besides the hemoglobin genotype 

 may also control the expression of the thalassemic genes. The pheno- 

 typic effects of the thalassemic genes are consistent with the hypothesis 

 of the amino acid substitution involving non-charged amino acids 

 (Ingram and Stretton, 1959b). However, no chemical alteration of the 

 hemoglobin of thalassemic patients has been reported so far. Few 

 research groups have been involved in the search for the hidden amino 

 acid substitution in tlialassemia, and tlie author is among tlunn. In spite 

 of extensive examination of the "Hb-A" from patients with thalassemia 

 major, no alteration of the fingerprinting pattern of this hemoglobin, 

 compared to Hb-A from noinial subjects, has yet been observed (C. 

 Baglioni, V. M. Ingram, and x\. O. W. Stretton, unpublished). The 

 analysis of the peptides of the "Hb-A" isolaterl from a sickle-cell/ 

 thalassemic patient has not revealed any difference in amino acid com- 

 position with peptides isolated from authentic Ilb-A (O. duidotti, per- 

 sonal communication). The evidence against the amino acid substitution 

 hypothesis is, how^ever, not conclusi\-e at all; moic wo'k and more chemi- 

 cal data are neces^ai-v before this possihilitv can be exclude(|. Tm-ersions 



