PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia.
Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.
In a previous report [Jacquet et al., 2005] we have shown that mild to moderate hyperprolinemia resulting from several alterations (either a complete deletion or missense mutations) of the proline dehydrogenase (PRODH) gene located on chromosome 22q11 is a risk factor for schizoaffective disorder but not for DSM3 R schizophrenia or bipolar disorder.
In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients.
Interestingly, three of the four alleles associated with or found in schizophrenia (V427M, L441P, and R453C) resulted in severe reduction of POX activity and hyperprolinemia.
These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus.