Linkage of alpha G-Philadelphia to alpha-thalassemia in African-Americans .

Abstract

ABSIRACT We have studied the inheritance of the a-chain hemoglobin variant Hb G-Philadelphia (a268AsILys#2) in two African-American families. Expression of the a-globin loci was monitored by the percentage of Hb G in these individuals. The variant represented approximately 33% of the total adult hemoglobin in some an 50% in others. a-Globin gene fragments were analyzed by using restriction endonucleases that cleave outside (EcoRI), within (HindIII), and between (Bgl II) the normal duplicated a-globin loci (aa/aa). Individuals having 33% variant lack one functioning a gene (aG/aa); those with 50% variant lack two genes, one missing on each chromosome (aG/a). Inheritance of aG was therefore linked to that of a chromosome with only one functional a-globin gene locus. This locus is probably the result of a nonhomologous crossover. Our results a so sugest equal expression of the a-globin loci in humans because the percentages of the variant could be explained solely on the basis of the total number of a genes present. The percentages of Hb G as well as other hematologic data all were consistent with the number of a-globin genes identified by restriction endonuclease mapping Gene mapping yields a more precise determination of the number of a-globin genes than does study of globin synthesis.The existence of two a-globin genes per haploid genome in humans is now well established (1, 2). Solution hybridization (3-6) and restriction endonuclease analyses of DNA (7-11) have shown that the most common cause of a-thalassemia is deletion of structural gene material, although nondeletion types also have been reported (12, 13). The four classical disorders due to a-thalassemia (silent carrier, a-thalassemia trait, Hb H disease, and hydrqps fetalis) are most frequently caused by deletion of one to four a-globin genes.In Asians, deletion of two a-globin genes on the same chromosome or of only one gene is common, whereas in Africans, deletion of only a single a-globin locus per chromosome is the predominant form (9, 10). The a-thalassemia syndromes in Asians commonly arise by gene deletion of either the 5' a-globin locus or both 5' and 3' a-globin loci; in Africans and Mediterraneans, as well as some Asians, generation of a single a-globin locus on a chromosome is due to a nonhomologous crossover (12,14).The most common a-chain variant in African-Americans is aCGPhiladelphia (aX68.Asn-bsy; aG), which has been reported to represent 20%, 30%, or 40% of the total.number of a-chains present (15). It has been suggested that this distribution may be due to the linkage of the variant a-globin gene to a-thalassemia (16, 17).We have investigated the expression of a-thalassemia in two African-American families with aG by using hematologic data, globin synthesis, and analyses of a-globin genes in restriction endonuclease digests of DNA. MATERIALS AND METHODSHematologic Studies. Nine individuals from two AfricanAmerican families were studied. In addition to aG, family 2 also had Hb S and f+-thalassemia genotypes (see Table 1). Hematologic stu...

Haemoglobin GPhiladelphia and its interaction with haemoglobin S and alpha-thalassaemia in Nigerians

“…This association had been described previously in other black populations (French & Lehman 1971, Bradley et al 1975, McCurdy et al 1975, Rieder et al 1976, Milner & Huisman 1976. The relative proportions of HbG in most of the Hb AG heterozygotes are also consistent with deletion of an a-globin gene (Surrey et al 1980, Sancar et al 1980. The globin gene analysis data prove conclusively that the ct-thalassaemia (deletion type) and aG Philadelphia genes are linked closely on the same chromosome ( -a G / ) in Nigerians.…”

“…In view of the well-known association between H b GPhiladelphia and a- thalassaemia (Minnich et al 1962, Martinez, Vidal & Colombo 1973, Schneider et al 1974, McCurdy et al 1975, Bradley, Wohl & Smith 1975, Rieder, Woodbury & Rucknagel 1976, Milner & Huisman 1976, Surrey et al 1980, Sancar et al 1980) the investigation of these Nigerian families offered us an opportunity to detect directly by globin gene-mapping the presence of a-thalassaemia and to demonstrate clearly for the first time its association with H b GPhiladelphia in an indigenous African population.…”

Linkage of the α^G Philadelphia Locus to α-Thalassemia in the Cuban Population

“…Several reports indicate that the former is indeed the case for Hb G Philadelphia [5][6][7], the most common a-chain variant among black popula tions [8]. These studies show that Hb G Philadelphia heterozygotes which synthesize 33% of the abnormal chain carry the variant gene linked to an a-thalassemia deletion.…”

“…Slight hematological alterations are therefore ob served in Hb G Philadelphia carriers. Gene analysis by restriction mapping allowed to demonstrate di rectly that these subjects have three a-globin genes [5,6].…”

Locus assignment of alpha-globin structural mutations by hybrid-selected translation.

“…This finding suggests that the four a-globin genes are equally expressed at the protein level. Levels of aglobin mutant significantly <25% can often be attributed to a relative instability of the mutant globin chain, while in some cases high levels may result from coexisting a-thalassemia in the genome, which lowers production of the normal a-globin chains (6)(7)(8). In a number of situations, however, the factors which contribute to the final level of a-globin mutant are not understood (7).…”