Diverse Point Mutations in the Human Glucose-6-phosphate Dehydrogenase Gene Cause Enzyme Deficiency and Mild or Severe Hemolytic Anemia

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 85; no. 14; pp. 5171 - 5175
• Main Authors: Vulliamy, T. J., D'Urso, M., Battistuzzi, G., Estrada, M., Foulkes, N. S., Martini, G., Calabro, V., Poggi, V., Giordano, R., Town, M., Luzzatto, L., Persico, M. G.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-07-1988; National Acad Sciences
• Subjects: 550401 - Genetics- Tracer Techniques; AMINO ACID SEQUENCE; AMINO ACIDS; Anemia, Hemolytic - enzymology; Anemia, Hemolytic - genetics; Anemias. Hemoglobinopathies; Base Sequence; BASIC BIOLOGICAL SCIENCES; Biochemistry; Biological and medical sciences; CARBOXYLIC ACIDS; Cloning, Molecular; DISEASES; Diseases of red blood cells; DNA; DNA SEQUENCING; ENZYMES; ETIOLOGY; Favism - enzymology; Favism - genetics; GENE MUTATIONS; Genetic mutation; Gin; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase - metabolism; Glucosephosphate Dehydrogenase Deficiency - genetics; Hematologic and hematopoietic diseases; HEMIACETAL DEHYDROGENASES; Hemolytic anemia; HEREDITARY DISEASES; Human genetics; HUMAN POPULATIONS; Humans; HYDROXY ACIDS; Male; Medical genetics; Medical sciences; Molecular Sequence Data; MOLECULAR STRUCTURE; Mutation; MUTATIONS; NUCLEIC ACIDS; ORGANIC ACIDS; ORGANIC COMPOUNDS; OXIDOREDUCTASES; PHENOTYPE; PHENYLALANINE; Point mutation; Polymorphism, Genetic; POPULATIONS; RECOMBINANT DNA; Sequencing; SERINE; STRUCTURAL CHEMICAL ANALYSIS; Human; Hemolytic anemia; Gene; Enzyme; Deficiency; Red blood cell; Glucose-6-phosphate dehydrogenase; Hemopathy; Mutation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.85.14.5171

Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is a common genetic abnormality affecting an estimated 400 million people worldwide. Clinical and biochemical analyses have identified many variants exhibiting a range of phenotypes, which have been well characterized from the hematological point of view. However, until now, their precise molecular basis has remained unknown. We have cloned and sequenced seven mutant G6PD alleles. In the nondeficient polymorphic African variant G6PD A we have found a single point mutation. The other six mutants investigated were all associated with enzyme deficiency. In one of the commonest, G6PD Mediterranean, which is associated with favism among other clinical manifestations, a single amino acid replacement was found (serine → phenylalanine): it must be responsible for the decreased stability and the reduced catalytic efficiency of this enzyme. Single point mutations were also found in G6PD Metaponto (Southern Italy) and in G6PD Ilesha (Nigeria), which are asymptomatic, and in G6PD Chatham, which was observed in an Indian boy with neonatal jaundice. In G6PD ``Matera,'' which is now known to be the same as G6PD A-, two separate point mutations were found, one of which is the same as in G6PD A. In G6PD Santiago, a de novo mutation (glycine → arginine) is associated with severe chronic hemolytic anemia. The mutations observed show a striking predominance of C → T transitions, with CG doublets involved in four of seven cases. Thus, diverse point mutations may account largely for the phenotypic heterogeneity of G6PD deficiency.