Abstract
Homozygous glucose phosphate isomerase (GPI) deficiency is one of the most important erythroenzymopathies causing hereditary non-spherocytic hemolytic anemia (HNSHA). We report an Indian patient with HNSHA showing 85 % reduction in GPI activity resulting from a homozygous missense replacement g.1459C > T in exon 16, leading to a substitution of the protein residue L487F mutation. This mutation has been detected previously in a compound heterozygous state along with another mutation in a GPI deficient patient elsewhere. To our knowledge, this is the first report of HNSHA associated with GPI deficiency with the homozygous L487F mutation, as well as the first report from India of GPI deficiency. Molecular modeling using the human crystal structure of GPI as a model was performed to determine how this mutation could affect enzyme structure and function. The enzyme is present in a dimeric form necessary for normal activity; the L487F mutation causes a loss of the ability of GPI to dimerize, which decreases the thermostability of the enzyme and results in significant changes in erythrocyte metabolism.
Similar content being viewed by others
References
Chaput M, Claes V, Portetelle D, Cludts I, Cravador A, Burny A, Gras H, Tartar A. The neurotrophic factor neuroleukin is 90 % homologous with phosphohexose isomerase. Nature. 1988;332:454–5.
Faik P, Walker JIH, Redmill AM, Morgan MJ. Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3′ sequences. Nature. 1988;332:455–7.
Xu W, Setter K, Feldman E, Ahmed T, Chiao JW. The differentiation and maturation mediator for human myeloid leukemia cells shares homology with neuroleukin or phosphoglucose isomerase. Blood. 1996;87:4502–6.
Beutler E, West C, Britton HA, Harris J, Forman L. Glucose phosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic hemolytic anemia (HNSHA). Blood Cells Mol Dis. 1997;23:402–9.
Ravindranath Y, Paglia DE, Warrier I, Valentine W, Nakatani M, Brockway RA. Glucose phosphate isomerase deficiency as a cause of hydrops fetalis. N Engl J Med. 1987;316:258–61.
Schroter W, Eber SW, Bardosi A, Gahr M, Gabriel M, Sitzmann FC. Generalized glucose phosphate isomerase (GPI) deficiency causing hemolytic anemia, neuromuscular symptoms and impairment of granulocytic function: a new syndrome due to a new stable GPI variant with diminished specific activity (GPI Homburg). Eur J Pediatr. 1985;144:301–5.
Read J, Pearce J, Li X, Muirhead H, Chirgwin J, Davies C. The crystal structure of human phosphoglucose isomerase at 1.6 A resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia. J Mol Biol. 2001;309:447–63.
Dacie JV, Lewis SM. Practical Haematology. London: Churchill Livingstone; 2009.
Beutler E, Blume KG, Kaplan JC, Lohr GW, Ramot B, Valentine WN. International Committee for Standardization in Haematology: recommended methods for red-cell enzyme analysis. Br J Haematol. 1977;35:331–40.
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning, a laboratory manual. 2nd ed. New York: Cold Spring Harbor Laboratory Press; 1989.
Baughan MA, Valentine WN, Paglia DE, Ways PO, Simons ER, DeMarsh QB. Hereditary hemolytic anemia associated with glucosephosphate isomerase (GPI) deficiency—a new enzyme defect of human erythrocytes. Blood. 1968;32:236–49.
Climent F, Roset F, Repiso A, Ossa P. Red cell glycolytic enzyme disorders caused by mutations: an update. Cardiovasc Haematol Disord Drug Targets. 2009;9:95–106.
Rossi F, Ruggiero S, Gallo M, Simeone G, Matarese SMR, Nobili B. Amoxicillin-induced hemolytic anemia in a child with glucose 6- phosphate isomerase deficiency. Ann Pharmacother. 2010;44:1327–9.
Xu W, Beutler E. The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia. J. Clin. Invest. 1994;94:2326–9.
Kanno H, Fujii H, Miwa S. Expression and enzymatic characterization of human glucose phosphate isomerase (GPI) variants accounting for GPI deficiency. Blood Cells Mol Dis. 1998;24:54–61.
Lin HY, Kao YH, Chen ST, Meng M. Effects of inherited mutations on catalytic activity and structural stability of human glucose-6-phosphate isomerase expressed in Escherichia coli. Biochim et Biophys Acta (BBA) Proteins Proteomics. 2009;1794:315–23.
Acknowledgments
This study was supported by Indian Council of Medical Research New Delhi.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Warang, P., Kedar, P., Ghosh, K. et al. Hereditary non-spherocytic hemolytic anemia and severe glucose phosphate isomerase deficiency in an Indian patient homozygous for the L487F mutation in the human GPI gene. Int J Hematol 96, 263–267 (2012). https://doi.org/10.1007/s12185-012-1122-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-012-1122-x