Alternative titles; symbols
HGNC Approved Gene Symbol: GPI
Cytogenetic location: 19q13.11 Genomic coordinates (GRCh38): 19:34,359,718-34,402,413 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.11 | Hemolytic anemia, nonspherocytic, due to glucose phosphate isomerase deficiency | 613470 | Autosomal recessive | 3 |
The GPI gene encodes glucose phosphate isomerase (GPI; EC 5.3.1.9), also known as phosphohexose isomerase (PHI; D-glucose-6-phosphate ketol-isomerase) and phosphoglucose isomerase (PGI). GPI catalyzes the interconversion of glucose-6-phosphate and fructose-6-phosphate, the second step of the Embden-Meyerhof glycolytic pathway. GPI is also referred to as neuroleukin (NLK) and autocrine motility factor (AMF) (Niinaka et al., 1998).
Chaput et al. (1988) cloned the gene for pig muscle phosphohexose isomerase and found 90% homology to the sequence of mouse neuroleukin. In a similar study, Faik et al. (1988) isolated a mouse phosphoglucose isomerase cDNA clone and found complete identity between 759 nucleotides at the 3-prime end of this clone and the sequence of mouse neuroleukin. Thus it seemed likely that the molecule previously described as neuroleukin was in fact glucose phosphate isomerase. Gurney (1988) found that mouse and human neuroleukin cDNAs expressed GPI enzyme activity when transfected into monkey COS cells.
Neuroleukin is a lymphokine produced by lectin-stimulated T cells. It induces immunoglobulin secretion by cultured human peripheral blood mononuclear cells. Neuroleukin acts early in the in vitro response that leads to formation of antibody-secreting cells. Continued production of immunoglobulin by differentiated antibody-secreting cells is neuroleukin-independent. NLK is not directly mitogenic; however, cellular proliferation is a late component of the response to this lymphokine. Gurney et al. (1986) found that NLK had no B-cell growth factor (BCGF) or B-cell differentiation factor (BCDF) activity in defined assays. Its induction of immunoglobulin secretion was found to be both monocyte- and T-cell-dependent. Gurney et al. (1986) found NLK in mouse salivary gland. It is a 56,000-dalton growth factor which is a neurotrophic factor as well as a lymphokine. It promotes the survival in culture of a subpopulation of embryonic spinal neurons that probably includes skeletal motor neurons. It also supports the survival of cultured sensory neurons that are insensitive to nerve growth factor but it has no effect on sympathetic or parasympathetic neurons. Gurney et al. (1986) found that the amino acid sequence of NLK is partly homologous to a highly conserved region of the external envelope protein of HTLV-III-LAV, the retrovirus that causes acquired immune deficiency syndrome (AIDS).
Niinaka et al. (1998) used protein microsequencing to show that the 55-kD autocrine motility factor (AMF) is NLK. Although AMF, NLK, and GPI have different assigned functions, they are the products of a single gene. Niinaka et al. (1998) cloned the human AMF cDNA. The gene encodes a 558-amino acid polypeptide. Niinaka et al. (1998) showed that the different sizes of AMF observed in normal versus cancerous cells are not the result of alternative splicing; the mRNAs are identical. Immunofluorescence studies showed that AMF is localized primarily in tubular vesicles in the cytoplasm. AMF and its receptor (AMFR; 603243) partially colocalize on the malignant cell surface.
Walker et al. (1995) and Xu et al. (1995) found that the GPI gene spans more than 40 kb and consists of 18 exons ranging in size from 44 to 153 bp. All splice sites conformed to the GT/AG rule.
Ritter et al. (1971) suggested that the PGI locus may be linked to the ABO locus. However, Hamerton et al. (1973) and McMorris et al. (1973) showed by somatic cell hybridization that the PGI locus is on chromosome 19. The SRO of 19cen-q13.2 was arrived at by data collated at HGM8 (Naylor et al., 1985). Lusis et al. (1985) assigned GPI to the long arm of chromosome 19. By study of human-mouse hybrid cells, Kaneda et al. (1987) narrowed the assignment of GPI to 19cen-q12.
Gurney (1988) reported that the cDNA encoding human neuroleukin maps to the same region as GPI on the long arm of chromosome 19.
In the mouse the hemoglobin beta chain locus is loosely linked to that for glucosephosphate isomerase (recombination fraction, 32%) on chromosome 7. GPI and PEPD, which are on chromosome 19 in man, are on chromosome 9 of the Chinese hamster, and TPI, which is on chromosome 12 of man, is on Chinese hamster chromosome 8 (Siciliano et al., 1983).
In a T-cell receptor transgenic mouse model, an inflammatory arthritis that resembles human rheumatoid arthritis (RA; 180300), is initiated by T cells but is sustained by antibodies to GPI. Using ELISA analysis, Schaller et al. (2001) detected high levels of antibody to GPI, independent of the presence of rheumatoid factor, in serum and synovial fluid of most RA patients; antibody to GPI was rare in controls and in patients with Lyme arthritis or Sjogren syndrome. In addition, the authors identified high levels of GPI in sera and synovial fluid and the presence of GPI-containing immune complexes in RA synovial fluid. Immunohistochemical analysis and confocal microscopy demonstrated intense expression of GPI on the surface of endothelial cells of synovial arterioles and some capillaries, but not venules or in other tissues. Intense patchy expression was observed on the surface lining of hypertrophic synovium, particularly where the hypertrophic villus formed; this expression pattern resembled that for vascular permeability factor (VEGF/VPF; 192240). Schaller et al. (2001) suggested that GPI may be presented to the immune system either on endothelial cell surfaces or as a soluble protein in synovial fluid of inflamed RA joints, leading to antibody binding or to immune complex formation with complement activation, respectively. In either case, they concluded that there is a role for autoantibody in the pathology of RA and that there may be scope for antibody treatments for the disease.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Mohrenweiser and Neel (1981) identified thermolabile variants of lactate dehydrogenase B, glucosephosphate isomerase, and glucose-6-phosphate dehydrogenase. None was detectable as a variant by standard electrophoretic techniques. All were inherited.
In a patient with chronic hemolytic anemia associated with severe deficiency of red cell glucose phosphate isomerase (613470), Walker et al. (1993) identified compound heterozygosity for 2 mutations in the GLI gene (172400.0001-172400.0002).
Schroter et al. (1985) identified the molecular basis of the variant GPI enzyme, GPI Homburg (see 172400.0006-172400.0007), previously described by Schroter et al. (1985) in a patient with severe GPI deficiency and neurologic deficits. The mutant enzyme had nearly normal stability, normal kinetic properties, and decreased electrophoretic mobility. The proband was a boy with transfusion-requiring, recurrent, spontaneous hemolytic crises beginning at the age of 3 and relieved by splenectomy at age 5 years. At age 13, however, he still had mild hemolytic anemia and moderate icterus and showed several pigment gallstones. Involvement of the neuromuscular system was indicated by muscle weakness, a mixed sensory and cerebellar ataxia, and mental retardation. Although granulocyte function appeared not to be altered in vivo, decreased production of superoxide anion and reduced bactericidal activity were observed in vitro. Although red cell enzymopathies are well-recognized causes of hemolytic anemia in the newborn, rarely have they been implicated in hydrops fetalis or even in immediate neonatal death.
McMorris et al. (1973) mapped the GPI gene to chromosome 19 and the MPI gene (154550) to chromosome 7; the mapping of the MPI gene to chromosome 7 was later retracted (Ruddle and McMorris, 1975).
In a patient with chronic nonspherocytic hemolytic anemia associated with severe deficiency of red cell glucose phosphate isomerase (613470), Walker et al. (1993) demonstrated compound heterozygosity for a transition converting codon 158 from GGC (gly) to AGC (ser) and codon 346 from CGC (arg) to CAC (his) (172400.0002).
For discussion of the arg346-to-his (R346H) mutation in the GPI gene that was found in compound heterozygous state in a patient with chronic nonspherocytic hemolytic anemia associated with severe deficiency of red cell glucose phosphate isomerase (613470) by Walker et al. (1993), see 172400.0001.
In a patient with chronic hemolytic anemia and severe deficiency of glucose phosphate isomerase (613470), Walker et al. (1993) demonstrated a T-to-C transition converting codon 524 from ATA (ile) to ACA (thr).
Kanno et al. (1996) reported a case of GPI deficiency associated with hemolytic anemia (613470) in a 3-year-old girl who presented in an acute hemolytic crisis after a history of prolonged neonatal jaundice. Red blood cell GPI activity was decreased to 11.8% of normal. Homozygosity for an asp539-to-asn missense mutation (GPI Fukuoka) was found.
Kanno et al. (1996) reported a case of GPI deficiency associated with hemolytic anemia (613470) in a 54-year-old man with chronic active hepatitis and compensated hemolysis. GPI activity was 18.8% of normal. Homozygosity for a thr224-to-met (GPI Iwate) missense mutation was found.
In a patient with severe GPI deficiency and neurologic deficits (613470), who was found by Schroter et al. (1985) to have a variant GPI enzyme (GPI Homburg), Kugler et al. (1998) identified compound heterozygous missense mutations in the GPI gene: an A-to-C transversion at nucleotide 59 in exon 1, causing a his-to-pro substitution at codon 20 (H20P), and a T-to-C transition at nucleotide 1016 in exon 12, causing a leu-to-pro substitution at codon 339 (L339P; 172400.0007). Kugler et al. (1998) proposed that the proline substitutions lead to incorrect folding, which would destroy both the catalytic (GPI) and neurotrophic (NLK) activities. Another patient they described with 2 missense mutations had no neurologic deficits; the mutations occurred in the catalytic site and should not have affected folding, supporting their hypothesis.
For discussion of the leu339-to-pro (L339P) mutation in the GPI gene that was found in a patient with severe GPI deficiency and neurologic deficits (613470) by Kugler et al. (1998), see 172400.0006.
Kanno et al. (1996) reported a Japanese patient with nonspherocytic hemolytic anemia and GPI deficiency (613470) who was homozygous for a gln343-to-arg (GPI Narita) mutation in the GLI gene.
Kanno et al. (1996) reported a Japanese patient with nonspherocytic hemolytic anemia and GPI deficiency (613470) who was homozygous for a thr5-to-ile (GPI Matsumoto) mutation in the GLI gene.
Kanno et al. (1996) reported a Japanese patient with nonspherocytic hemolytic anemia and GPI deficiency (613470) who was compound heterozygous for a 2 mutations in the GLI gene: thr375 to arg (T375R) and asp539 to asn (D539N; 172400.0011). This variant was designated GPI Kinki.
For discussion of the asp539-to-asn (D539N) mutation in the GPI gene that was found in compound heterozygous state in a patient with nonspherocytic hemolytic anemia and GPI deficiency (613470) by Kanno et al. (1996), see 172400.0010.
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