PRODH mutations and hyperprolinemia in a subset of schizophrenic patients.
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.
Jacquet
Hélène
H
INSERM EMI 9906, IRFMP, Faculty of Medicine, 76183 Rouen, France.
Raux
Grégory
G
Thibaut
Florence
F
Hecketsweiler
Bernadette
B
Houy
Emmanuelle
E
Demilly
Caroline
C
Haouzir
Sadeq
S
Allio
Gabrielle
G
Fouldrin
Gael
G
Drouin
Valérie
V
Bou
Jacqueline
J
Petit
Michel
M
Campion
Dominique
D
Frébourg
Thierry
T
D019943:Amino Acid Substitution; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011392:Proline / Q000097:blood* / Q000235:genetics; D011394:Proline Oxidase / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion
D011392:Proline; D011394:Proline Oxidase