Studies on Pathophysiology of Schizophrenia with a Rare Variant as a Clue

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Schizophrenia is a relatively common and severe mental disorder with
complex inheritance patterns; its main manifestations are
hallucinations, delusions, and disorganized speech and thinking. The
exact etiology of schizophrenia remains unsolved, although
pharmacological and biological studies have proposed several
hypothetical disease mechanisms and plausible candidate genes for
susceptibility. Since the early nineties, extensive genetic studies
have been performed on this illness, but there has been no marked
progress in the research, and reproducible results have not yet been
obtained. Such difficulties in genetic studies of schizophrenia arise
from the heterogeneity of this disease. Candidate gene approaches are
based on the common disease-common variant hypothesis. However, there
is no guarantee that a common variant is shared by patients with
heterogeneous pathophysiologies of this disorder. We studied a rare
mutation with a major alteration in genetic function based on the
common disease-rare variant hypothesis. We detected a novel frameshift
mutation of glyoxalase 1 (GLO1) accompanied by a 50% reduction in
enzymatic activities in a male schizophrenic patient belonging to a
pedigree with multiple affected individuals. GLO1 detoxifies toxic
carbonyl compounds that produce advanced glycation end products (AGEs)
such as pentosidine by Maillard reaction. AGEs accumulate because of
carbonyl stress caused by an increase in reactive carbonyl compounds
and their attendant protein modifications. A significant increase in
plasma AGEs and a low serum pyridoxal level was seen in our patient.
In addition, we found other patients with schizophrenia characterized
by the presence of homozygotes of the Ala allele of Glu111Ala in the
GLO1 gene and a 16% reduction in the activities that showed high
plasma AGEs. As compared to that of the 61 control patients, 45
patients with schizophrenia yielded significantly high levels of AGEs
in the plasma and low serum pyridoxal levels. Our findings suggest
that GLO1 deficits and carbonyl stress are linked to the development
of a certain subtype of schizophrenia. Elevated plasma pentosidine and
concomitant low vitamin B₆ levels can be the most cogent
and easily measurable biomarkers in schizophrenia and can prove to be
helpful for classifying heterogeneous schizophrenia on the basis of
biological causes.