MOLECULAR ANALYSIS OF GLUCOSE PHOSPHATE ISOMERASE DEFICIENCY ASSOCIATED WITH HEREDITARY HEMOLYTIC-ANEMIA

We report here two new cases of glucose phosphate isomerase (GPI) defi ciency associated with hemolytic anemia and present the results of mol ecular analysis of the five Japanese GPI variants. A Japanese girl (GP I Fukuoka) had an episode of prolonged neonatal jaundice and at 3 year s of age was admitted due to acute hemolytic crisis occurring with upp er respiratory tract infection. Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level o f RBCs was slightly decreased. A 54-year-old Japanese man (GPI Iwate) was hospitalized due to chronic active hepatitis, and compensated hemo lysis 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. Sequen cing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG --> CGG (343Gln --> Arg), 14ACC --> ATC (5Thr --> IIe), 671ACG --> ATG (224Thr --> Met), and 1615GAC --> AAC (539Asp --> Asn) in GPI Narita, GPI Matsumoto, GPI Iwate, and GPI Fukuoka, respectively. We a lso identified GPI Kinki as a compound heterozygote of 1124ACA --> AGA (375Thr --> Arg)/1615GAC --> AAC(539Asp --> Asn). Our findings, togeth er with the previous results of other investigators, showed that the G PI gene mutations so far identified were heterogeneous, although most GPI variants had common biochemical characteristics such as heat insta bility and normal kinetics. Several amino acid substitutions were iden tified in the proximity of the catalytically important amino acid resi dues such as Ser/Asp 159/160, Asp341, and Lys518, which have been iden tified in the structural analysis of the pig GPI. The molecular charac terization of human GPI variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as t he Structure-function relationship of this enzyme. (C) 1996 by The Ame rican society of Hematology.