scholarly journals The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.

1994 ◽  
Vol 94 (6) ◽  
pp. 2326-2329 ◽  
Author(s):  
W Xu ◽  
E Beutler
Keyword(s):  
Hemolytic Anemia ◽  
Gene Mutations ◽  
Glucose Phosphate Isomerase ◽  
Glucose Phosphate ◽  
Chronic Hemolytic Anemia

Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2321-2325 ◽  
Author(s):  
H Kanno ◽  
H Fujii ◽  
A Hirono ◽  
Y Ishida ◽  
S Ohga ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hemolytic Anemia ◽  
Molecular Analysis ◽  
Gene Mutations ◽  
Mean Value ◽  
Missense Mutations ◽  
Glucose Phosphate Isomerase ◽  
Upper Respiratory Tract ◽  
Important Amino Acid ◽  
Glucose Phosphate

We report here two new cases of glucose phosphate isomerase (GPI) deficiency associated with hemolytic anemia and present the results of molecular analysis of the five Japanese GPI variants. A Japanese girl (GPI Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute hemolytic crisis occurring with upper respiratory tract infection. Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (GPI Iwate) was hospitalized due to chronic active hepatitis, and compensated hemolysis was noted. RBC GPI activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG-->CGG (343Gln-->Arg), 14ACC-->A7C (5Thr-- >lle), 671ACG-->A7G (224Thr-->Met), and 1615GAC-->AAC (539Asp-->Asn) in GPI Narita, GPI Matsumoto, GPI Iwate, and GPI Fukuoka, respectively. We also identified GPI Kinki as a compound heterozygote of 1124ACA-- >AGA(375Thr-->Arg)/ 1615GAC-->AAC(539Asp-->Asn). Our findings, together with the previous results of other investigators, showed that the GPI gene mutations so far identified were heterogeneous, although most GPI variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig GPI. The molecular characterization of human GPI variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the structure-function relationship of this enzyme.

scholarly journals Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2306-2310 ◽  
Author(s):  
L Baronciani ◽  
A Zanella ◽  
P Bianchi ◽  
M Zappa ◽  
F Alfinito ◽  
...  
Keyword(s):  
Amino Acids ◽  
Hemolytic Anemia ◽  
Normal Subjects ◽  
Common Mutation ◽  
Missense Mutations ◽  
Glucose Phosphate Isomerase ◽  
Molecular Defects ◽  
Glucose Phosphate ◽  
Conserved Amino Acids ◽  
Chronic Hemolytic Anemia

We have studied four unrelated Italian patients with chronic hemolytic anemia associated with glucose phosphate isomerase (GPI) deficiency. Using intronic primers, we were able to detect the gene alterations on the genomic DNA of the patients. Five different mutations were identified among the eight mutated alleles found: three missense mutations (301A,584T,1028G), one nonsense mutation (286T), and a four nucleotides deletion [Del 1473-IVS16(+2)]. All of these were new except for mutation 1028G, which was previously identified in a Japanese variant (GPI Narita). Two patients were homozygotes (301A/301A and 1028G/1028G), whereas the other two were compound heterozygotes sharing a common mutation [286T/584T and Del 1473-IVS16(+2)/584T]. The missense mutations were found to involve highly conserved amino acids, suggesting that these residues are crucial for the maintenance of the enzyme function. The mutation 286T results in a truncated protein of 95 amino acids in comparison with the 558 of the normal one. The four nucleotides deletion located at the junction of exon/intron 16(5′- TTGGTCGgtgagt-3′) is the first GPI mutation affecting a splice site. Moreover one difference from the published sequence (473T-->G) was found in exon five in all of the eight alleles studied and in 30 normal subjects. Correlation was made between mutations, biochemical characteristics of the enzyme, and clinical course of the disease.

Characterization of the 5′ end of the gene for human glucose phosphate isomerase (GPI)

Genomics ◽  
1990 ◽  
Vol 7 (4) ◽  
pp. 638-643 ◽  
Author(s):  
James I.H. Walker ◽  
Pelin Faik ◽  
Michael J. Morgan
Keyword(s):  
Glucose Phosphate Isomerase ◽  
Glucose Phosphate

Preparation and characterization of immobilized glucose-phosphate isomerase

1986 ◽  
Vol 8 (4) ◽  
pp. 222-226 ◽  
Author(s):  
L.M. Simon ◽  
M. Kotormán ◽  
B. Szajáni ◽  
L. Boross
Keyword(s):  
Glucose Phosphate Isomerase ◽  
Glucose Phosphate

Red cell glucose phosphate isomerase (GPI): a molecular study of three novel mutations associated with hereditary nonspherocytic hemolytic anemia

2006 ◽  
Vol 27 (11) ◽  
pp. 1159-1159 ◽  
Author(s):  
Ada Repiso ◽  
Baldomero Oliva ◽  
Joan-Lluis Vives-Corrons ◽  
Ernest Beutler ◽  
José Carreras ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Molecular Study ◽  
Red Cell ◽  
Glucose Phosphate Isomerase ◽  
Novel Mutations ◽  
Glucose Phosphate ◽  
Cell Glucose

Glucose Phosphate Isomerase Deficiency In 2 Patients With Novel Mutations Presenting As Severe Neurologic Abnormalities and Transfusion Dependent Hemolytic Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 947-947 ◽  
Author(s):  
Mammen Puliyel ◽  
Patrick G. Gallagher ◽  
Vasilios Berdoukas ◽  
Bertil Glader ◽  
Thomas Coates
Keyword(s):  
Developmental Delay ◽  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Cerebral Atrophy ◽  
Global Developmental Delay ◽  
Glucose Phosphate Isomerase ◽  
Hematopoietic Stem ◽  
Neurologic Symptoms ◽  
Glucose Phosphate

Abstract Introduction Glucose phosphate isomerase (GPI) deficiency is the third most common red cell enzymopathy. GPI is an enzyme that reversibly catalyzes the conversion of glucose-6-phosphate into fructose 6-phosphate in the second step of glycolysis. Patients afflicted by GPI deficiency have chronic hemolysis and may also suffer from acute hemolytic crises. There are 184 known mutations of the GPI gene and to date, a neurological deficit is found in only five patients and only two of these have been characterized at a molecular level. We report 2 patients with previously unknown mutations of the GPI gene associated with, severe neurologic abnormalities and hemolytic anemia. Case 1 He was born at 38 weeks gestation; marked pallor and hepatosplenomegaly were noted at birth. The bilirubin was elevated at birth (indirect 7.5 mg/dl and direct 2.2mg/dl) requiring phototherapy. He has transfusion dependent anemia since birth. Enzymes studied were performed which showed GPI levels of 2.02 EU/gm hb ( normal range 16.3-24.7 ) and elevated glucose 6 phosphate dehydrogenase , pyruvate kinase and hexokinase. The pyrimidine 5'-nucleotidase screen was normal. In his subsequent course, he started to have seizures at 6 months of age, refractory to anticonvulsant therapy. He has severe hypotonia and global developmental delay. Magnetic resonance imaging of the brain showed generalized cerebral atrophy with no evidence of kernicterus. Case 2 He was noted to have anemia and marked hepatosplenomegaly at birth. He required exchange transfusions and phototherapy in the neonatal period. He has subsequently suffered from lifelong transfusion-dependent hemolytic anemia. He also suffers from developmental delay, ataxia, spasticity, and seizures. Of note, MRI did not exhibit evidence of kernicterus. The mutations were predicted to be pathogenic (probably damaging) by PolyPhen. Both these mutations were in a highly conserved residue. Genetic probe for preimplantation diagnosis is being used for selection of an embryo which is does not have GPI deficiency and is also a potential HLA match with the hope of undergoing hematopoietic stem cell transplantation to avoid the complications of chronic transfusions and iron overload. Discussion GPI has many functions. In dimeric form, it exhibits its catalytic function. In monomeric form, it acts as a neurotrophic growth factor, neuroleukin, which in vitro promotes survival of neurons. Abnormalities in neuroleukin have been found in motor neuron disease and in patients with central nervous system abnormalities in patients with acquired immunodeficiency disease. These effects of GPI/neuroleukin and relative deficiency in brain and neurons of this protein may explain the neurologic presentation. Decreased phosphatide phosphatase 1 activity, a lipogeneic enzyme due to mTOR activation by accumulated glucose-6-phosphate has been suggested to contribute to the neurologic symptoms. Why some of these mutation are associated with neurologic deficits while most others are not is not known. It has been speculated that the mutations which affect the folding may cause altered structure and function causing neurologic symptoms as well as hemolytic anemia while mutations affecting the catalytic site presents only as hemolytic anemia without neurologic symptoms. Disclosures: No relevant conflicts of interest to declare.

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