Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency

Abstract

Glucose-6-phosphate isomerase (GPI) deficiency, an autosomal recessive genetic disorder with the typical manifestation of nonspherocytic haemolytic anaemia, can be associated in some cases with neurological impairment. GPI has been found to be identical to neuroleukin (NLK), which has neurotrophic and lymphokine properties. To focus on the possible effects of GPI mutations on the central nervous system through an effect on neuroleukin activity, we analysed DNA isolated from two patients with severe GPI deficiency, one of them with additional neurological deficits, and their families. The neurologically affected patient (GPI Homburg) is compound heterozygous for a 59 A-->C (H20P) and a 1016 T-->C (L339P) exchange. Owing to the insertion of proline, the H20P and L339P mutations are likely to affect the folding and activity of the enzyme. In the second family studied, the two affected siblings showed no neurological symptoms. The identified mutations are 1166 A-->G (H389R) and 1549 C-->G (L517V), which are located at the subunit interface. We propose that mutations that lead to incorrect folding destroy both catalytic (GPI) and neurotrophic (NLK) activities, thereby leading to the observed clinical symptoms (GPI Homburg). Those alterations at the active site, however, that allow correct folding retain the neurotrophic properties of the molecule (GPI Calden).

Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase

“…The erythrocytes are adversely affected in these patients probably due to their dependence on glycolysis for ATP production. In some severe GPI deficiencies, neuromuscular dysfunction is observed (57). The link between GPI deficiency and neuromuscular dysfunction has not been established (10).…”

“…The link between GPI deficiency and neuromuscular dysfunction has not been established (10). The reduced potency of GPI as a cytokine has been proposed to account for this (57). Alternatively, the marked hyperbilirubinemia and tissue hypoxia as a result of severe anemia have been implicated (58).…”

The crystal structure of a multifunctional protein: Phosphoglucose isomerase/autocrine motility factor/neuroleukin

“…PGI deficiency in humans leads to nonspherocytic hemolytic disease (1,2). In addition, the serum activity of PGI has been established as a tumor marker in human cancer patients (3,4), and elevation in PGI activity is closely correlated with metastasis (5,6).…”

An infant with chronic hemolytic anemia

“…Glucose phosphate isomerase plays a role as a neurotrophic factor for spinal and sensory neurons in its monomeric form in addition to its enzymatic activity. Thus neu- rodegenerative diseases associated with muscle weakness, ataxia, dysarthria and mental retardation may be observed in addition to hemolytic anemia in its deficiency (7). In addition, granulocyte disorders and splenomegaly have been reported in some patients (8).…”