Genetic Control of Haemoglobin Synthesis and the Haemoglobinopathies

The genes for the a-globins are located on the short arm of chromosome 16. The order of the genes on the chromosome is determined when they appear during development (Figure HA.3). There are also pseudogenes that during evolution have acquired mutations and are not expressed (y Z, W a1 and y a2). After 8 weeks of embryonic development there are two functional a chain genes per chromosome (a1 and a2) which are normally expressed equally. Hence, there are four functioning a genes in each erythroid precursor.

The P-globin gene cluster is located on the short arm of chromosome 11, there is a single pseudogene in this cluster (y P). While there are two genes controlling expression of y-chains (y G and y A), which are present in foetal haemoglobin, there is only a single functional P-chain gene per chromosome. The chain structure of human haemoglobins is given in Figure HA.4.

Alteration of the coding regions (exons) of the globin genes is likely to alter the amino acid sequence of the corresponding globin chain, the end result is a haemoglobinopathy (e.g. sickle cell disease). On the other hand, if there is lack of expression of a globin chain as a result of deletion or mutation at critical control regions (e.g. RNA splice sites) then a thalassaemia results. Although sickle cell and thalassaemia are the two most common anomalies of haemoglobin, there are other abnormal forms:

• Haemoglobin C—homozygotes have a mild haemolytic anaemia and splenomegaly. Heterozygotes are asymptomatic

Figure HA.3 Genes responsible for haemoglobin synthesis


Figure HA.4

• Haemoglobin E—homozygotes have mild anaemia with thalassaemic indices (low MCV, low MCH). Heterozygotes have thalassaemic indices

• Haemoglobins with altered oxygen affinity (rare)—if increased, polycythaemia results (e.g. Hb Chesapeake) and if decreased mild (asymptomatic) anaemia is noted (e.g. Hb Kansas)

• Unstable haemoglobins (rare)—autosomal-dominant traits that present as congenital Heinz body haemolytic anaemia or after oxidant stress, e.g. after treatment with sulphonamides, e.g. Hb Zurich

• M Haemoglobins (rare)—favour the oxidized iron state (Fe3+) and, therefore, have congenital methaemoglobinaemia. Present as familial cyanosis.

Sickle Cell Disease

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