Human Molecular Genetics, 2002, Vol. 11, No. 19 2243-2249
© 2002 Oxford University Press
PRODH mutations and hyperprolinemia in a subset of schizophrenic patients
1INSERM EMI 9906, IRFMP, Faculty of Medicine, 76183 Rouen, France, 2Department of Psychiatry, CH du Rouvray and CHU de Rouen, 76031 Rouen, France, 3Department of Biochemistry and 4Department of Genetics, CHU de Rouen, 76031 Rouen, France
Received April 16, 2002; Accepted July 12, 2002
The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11. Screening for genomic rearrangements of 23 genes within or at the boundaries of the DGCR in 63 unrelated schizophrenic patients and 68 unaffected controls, using quantitative multiplex PCR of short fluorescent fragments (QMPSF), led us to identify, in a family including two schizophrenic subjects, a heterozygous deletion of the entire PRODH gene encoding proline dehydrogenase. This deletion was associated with hyperprolinemia in the schizophrenic patients. In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels. Segregation analysis within the two families harboring respectively the PRODH deletion and the L441P mutation showed that the presence of a second PRODH nucleotide variation resulted in higher levels of prolinemia. In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient. 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.
* To whom correspondence should be addressed at: INSERM EMI 9906, Faculty of Medicine, 22 Boulevard Gambetta, 76183 Rouen, France. Tel: +33 235148280; Fax: +33 235148237; Email: dominique.campion{at}univ-rouen.fr
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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