See Kirkman et al. (1964), Ben-Bassat and Ben-Ishay (1969), Lenzerini et al. (1969), Testa et al. (1980), and Morelli et al. (1984). A change from cytosine to thymine at base position 563 (in exon 6) causes a change from serine to phenylalanine in amino acid position 188 (Vulliamy et al., 1988). De Vita et al. (1989) found that G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari have the same mutational change, resulting from a TCC-to-TTC mutation in exon 6. There is a second silent mutation of TAC-to-TAT at codon 437 in exon 11 (C-to-T at nucleotide 1311; see 305900.0018); both codons code for tyrosine. This mutation is a polymorphism, causes class 2 abnormality, and creates a new MboII site.
Beutler and Kuhl (1990) studied the distribution of the nucleotide polymorphism C1311T in diverse populations. Only 1 of 22 male subjects from Mediterranean countries who had the G6PD Mediterranean-563T genotype had a C at nucleotide 1311, which is the more frequent finding in this group. In contrast, both G6PD Mediterranean-563T males from the Indian subcontinent had the usual C at nucleotide 1311. Beutler and Kuhl (1990) interpreted these findings as suggesting that the same mutation at nucleotide 563 arose independently in Europe and in Asia.
Similar studies were done by Kurdi-Haidar et al. (1990) in 21 unrelated individuals with G6PD Mediterranean from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel. All but 1 had the 563 mutation, and, of these, all but 1 had the C-to-T change at nucleotide 1311. Among another 24 unrelated Middle Eastern persons with normal G6PD activity, 4 had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. Kurdi-Haidar et al. (1990) concluded that most Middle Eastern subjects with the G6PD Mediterranean phenotype have the same mutation as that found in Italy; that the silent mutation is an independent polymorphism in the Middle East, with a frequency of about 0.13; and that the mutation leading to G6PD Mediterranean deficiency probably arose on a chromosome that already carried the silent mutation.
In Nepal, Matsuoka et al. (2003) tested 300 males for G6PD deficiency and identified 2 (0.67%) who were G6PD deficient. Compared with normal controls, G6PD activity was 12% and 26%, respectively. Both subjects had the 563C-T substitution of G6PD Mediterranean (ser188 to phe), and both had the silent 1311C-T change. A similar second change has been described in persons living in Mediterranean countries and Middle East countries. However, the form of G6PD Mediterranean found in India and Pakistan has no replacement at nucleotide 1311. Thus, the 2 subjects in Kathmandu, Nepal, would be closer to people in Middle East countries than people in India.
Corcoran et al. (1992) described a G6PD mutant biochemically indistinguishable from the common variety due to a C-to-T mutation at nucleotide 563. Instead, a C-to-T transition was found at nucleotide 592 in exon 6, changing an arginine residue to a cysteine residue only 10 amino acids downstream from the Mediterranean mutation. The new variant was named G6PD Coimbra (305900.0031).
Kaplan et al. (1997) presented data suggesting that the coexistence of Mediterranean type G6PD deficiency with the TA insertion polymorphism of the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome (143500) in adults, is responsible for the development of neonatal hyperbilirubinemia. This is the most devastating clinical consequence of G6PD deficiency; it can be severe and result in kernicterus or even death. Kaplan et al. (1997) found that neither G6PD deficiency nor the polymorphism of UDP glucuronosyltransferase alone increased the incidence of neonatal hyperbilirubinemia, but in combination they did. The authors suggested that this gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.
Kaplan et al. (2001) reported 2 premature female neonates heterozygous for the G6PD Mediterranean mutation who presented with severe hyperbilirubinemia requiring exchange transfusions. Both had had normal G6PD biochemical screening tests.