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

Glucose-6-phosphate isomerase (GPI) deficiency, an autosomal recessive gene tic disorder with the typical manifestation of nonspherocytic haemolytic an aemia, can be associated in some cases with neurological impairment. GPI ha s been found to be identical to neuroleukin (NLK), which has neurotrophic a nd lymphokine properties. To focus on the possible effects of GPI mutations on the central nervous system through an effect on neuroleukin activity, w e analysed DNA isolated from two patients with severe GPI deficiency, one o f them with additional neurological deficits, and their families. The neuro logically affected patient (GPI Homburg)is compound heterozygous fora 59 A- ->C (H20P) and a 1016 T-->C (L339P) exchange. Owing to the insertion of pro line, the H20P and L339P mutations are likely to affect the folding and act ivity of the enzyme. In the second family studied, the two affected sibling s 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 cata lytic (GPI) and neurotrophic (NLK) activities, thereby leading to the obser ved clinical symptoms (GPI Homburg). Those alterations at the active site, however, that allow correct folding retain the neurotrophic properties of t he molecule (GPI Gal; den).