IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 451 



3. The Molecular Basis of Thalassemia 



The main pathological manifestation of thalassemia is the failure to 

 produce red cells with a normal hemoglobin content. The total red cells 

 production is increased (Bailey and Prankerd, 1958 1, hut in a way 

 insufficient to compensate for the decreased hemoglol)in content of the 

 red cells. 



The decrease in hemoglobin synthesis is at the expense of Hb-A 

 only: abnormal hemoglobins, found in heterozygous combination with 

 thalassemia, are produced at a normal rate, so that defects of the heme 

 synthesis or of other enzymatic mechanisms seem unlikely in these cases. 



Abnormal hemoglobins are usually found in lower amounts than 

 Hb-A in heterozygotes for an abnormal hemoglobin gene. It is assumed 

 that the lower rate of synthesis of abnormal hemoglobins relative to 

 Hb-A is the consequence of the gene mutation. The ratio Hb-A/abnormal 

 hemoglobin is, however, quite variable, from close to 1 to 4 or more 

 (see Section V,A,2). One can thus imagine instances where a hemoglobin 

 gene mutation produces such drastic alterations that the corresponding 

 abnormal hemoglobin cannot be made at all or is made at a very 

 low rate. 



Itano (1956), and in more detail Ingram and Stretton (1959b), have 

 suggested that the drastic reduction in Hb-A synthesis in thalassemia 

 may result from an alteration or an amino acid substitution (Ingram 

 and Stretton, 1959b), not involving a change of the electrophoretic 

 charge of the hemoglobin molecule. 



Either peptide chain of Hb-A could be involved by such alteration 

 and two types of thalassemia can be defined (Ingram and Stretton, 

 1959b) : (a) a chain thalassemia, allelic to the a locus, which impairs 

 the synthesis of a chains; (b) p chain thalassemia, allelic to the f^ locus, 

 which impairs the synthesis of (3 chains. This hypothesis provides an 

 explanation for most of the alterations of the hemoglobin pattern in 

 thalassemia. In the a chain thalassemia a reduced amount of ao dimers 

 is available to combine with ^^^ and 82'^- dimers or with any abnormal 

 type of /32 dimers, like jSo^ or j32^. Consequently, the rate of synthesis of 

 Hb-A, Hb-Ao, and of any other hemoglobin containing a^ dimers will be 

 equally lowered and the relative proportion of these hemoglobins will 

 be unchanged from the normal; the a chain thalassemia is in fact of a 

 non-increased Hb-Ao and non-interacting with /? chain abnormality 

 type. On the contrary, the a chain thalassemia will interact with « chain 

 abnormal genes, like a^ (Atwater et al., 1960b). The balance in the rate 

 of synthesis of a chain versus ^, y, and 8 chains is profoundly altered 

 in a thalassemia; /?•., yo, and 80 dimers are produced in large excess over 



