Glucose Phosphate Isomerase Deficiency: High Prevalence of p.Arg347His Mutation in Indian Population Associated with Severe Hereditary Non-Spherocytic Hemolytic Anemia Coupled with Neurological Dysfunction
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Glucose-6-phosphate isomerase (GPI) deficiency is an autosomal recessive genetic disorder causing hereditary non-spherocytic hemolytic anemia (HNSHA) coupled with a neurological disorder. The aim of this study was to identify GPI genetic defects in a cohort of Indian patients with HNSHA coupled with neurological dysfunction.
Thirty-five patients were screened for GPI deficiency in the HNSHA patient group; some were having neurological dysfunction. Enzyme activity was measured by spectrophotometric method. The genetic study was done by single-stranded conformation polymorphism (SSCP) analysis, restriction fragment length polymorphism (RFLP) analysis by the restriction enzyme AciI for p.Arg347His (p.R347H) and confirmation by Sanger’s sequencing.
Out of 35 patients, 15 showed 35% to 70% loss of GPI activity, leading to neurological problems with HNSHA. Genetic analysis of PCR products of exon 12 of the GPI gene showed altered mobility on SSCP gel. Sanger’s sequencing revealed a homozygous c1040G > A mutation predicting a p.Arg347His replacement which abolishes AciI restriction site. The molecular modeling analysis suggests p.Arg347 is involved in dimerization of the enzyme. Also, this mutation generates a more labile enzyme which alters its three-dimensional structure and function.
This report describes the high prevalence of p.Arg347His pathogenic variant identified in Indian GPI deficient patients with hemolytic anemia and neuromuscular impairment. It suggests that neuromuscular impairment with hemolytic anemia cases could be investigated for p.Arg347His pathogenic variant causing GPI deficiency because of neuroleukin activity present in the GPI monomer which has neuroleukin action at the same active site and generates neuromuscular problems as well as hemolytic anemia.
KeywordsGlucose-6-phosphate isomerase (GPI) deficiency Neurological dysfunction Hereditary non-spherocytic hemolytic anemia (HNSHA) Glycolysis Molecular modeling India
PSK: Designed the experiment. RMD, AC, RD, PC, VG: Collected the biochemical, hematological data and performed lab experiments. HP, AS, SB, SC: Referred the case and did clinical examinations. PSK, PW, RD: Conducted the literature search, designed the figures and tables, and analyzed and interpreted the data. PSK, RD: Revised the first draft and completed the final manuscript. All authors approved the final manuscript. PC, VG, RD, AC, PW, PSK prepared the manuscript. MM is the Director, NIIH and also a clinician. She gave her suggestion about the cases and helped in clinical correlation; All authors read and approved the final manuscript. PSK is the guarantor.
Compliance with Ethical Standards
Conflict of Interest
Source of Funding
This study was performed with the financial support from Indian Council of Medical Research, New Delhi, and Department of Biotechnology, New Delhi.
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