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

Prabhakar S. Kedar, Rashmi Dongerdiye, Pooja Chilwirwar, Vinod Gupta, Ashish Chiddarwar, Rati Devendra, Prashant Warang, Harsha Prasada, Abhilasha Sampagar, Sunil Bhat, S. Chandrakala, Manisha Madkaikar

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)692-699
Number of pages8
JournalIndian Journal of Pediatrics
Volume86
Issue number8
DOIs
Publication statusPublished - 01-08-2019
Externally publishedYes

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xylose isomerase
Glucose-6-Phosphate Isomerase
Phosphates
Mutation
Population
Hemolytic Anemia
Enzymes
Hereditary spherocytic hemolytic Anemia
Restriction Mapping
Inborn Genetic Diseases
Dimerization
Nervous System Diseases

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Kedar, Prabhakar S. ; Dongerdiye, Rashmi ; Chilwirwar, Pooja ; Gupta, Vinod ; Chiddarwar, Ashish ; Devendra, Rati ; Warang, Prashant ; Prasada, Harsha ; Sampagar, Abhilasha ; Bhat, Sunil ; Chandrakala, S. ; Madkaikar, Manisha. / 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. In: Indian Journal of Pediatrics. 2019 ; Vol. 86, No. 8. pp. 692-699.
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title = "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",
abstract = "Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.",
author = "Kedar, {Prabhakar S.} and Rashmi Dongerdiye and Pooja Chilwirwar and Vinod Gupta and Ashish Chiddarwar and Rati Devendra and Prashant Warang and Harsha Prasada and Abhilasha Sampagar and Sunil Bhat and S. Chandrakala and Manisha Madkaikar",
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Kedar, PS, Dongerdiye, R, Chilwirwar, P, Gupta, V, Chiddarwar, A, Devendra, R, Warang, P, Prasada, H, Sampagar, A, Bhat, S, Chandrakala, S & Madkaikar, M 2019, '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', Indian Journal of Pediatrics, vol. 86, no. 8, pp. 692-699. https://doi.org/10.1007/s12098-019-02928-1

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. / Kedar, Prabhakar S.; Dongerdiye, Rashmi; Chilwirwar, Pooja; Gupta, Vinod; Chiddarwar, Ashish; Devendra, Rati; Warang, Prashant; Prasada, Harsha; Sampagar, Abhilasha; Bhat, Sunil; Chandrakala, S.; Madkaikar, Manisha.

In: Indian Journal of Pediatrics, Vol. 86, No. 8, 01.08.2019, p. 692-699.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glucose Phosphate Isomerase Deficiency

T2 - High Prevalence of p.Arg347His Mutation in Indian Population Associated with Severe Hereditary Non-Spherocytic Hemolytic Anemia Coupled with Neurological Dysfunction

AU - Kedar, Prabhakar S.

AU - Dongerdiye, Rashmi

AU - Chilwirwar, Pooja

AU - Gupta, Vinod

AU - Chiddarwar, Ashish

AU - Devendra, Rati

AU - Warang, Prashant

AU - Prasada, Harsha

AU - Sampagar, Abhilasha

AU - Bhat, Sunil

AU - Chandrakala, S.

AU - Madkaikar, Manisha

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

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