title: Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome.
abstract: Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). 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.
authors.affiliation: Department of Genetics and Inserm U614, IFRMP, Faculty of Medicine, Rouen, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Raux
authors.forename: Emilie
authors.initials: E
authors.lastname: Bumsel
authors.forename: Bernadette
authors.initials: B
authors.lastname: Hecketsweiler
authors.forename: Therese
authors.initials: T
authors.lastname: van Amelsvoort
authors.forename: Janneke
authors.initials: J
authors.lastname: Zinkstok
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier-Hanu
authors.forename: Carole
authors.initials: C
authors.lastname: Fantini
authors.forename: Georges-Marie M
authors.initials: GM
authors.lastname: Brévière
authors.forename: Gabriella
authors.initials: G
authors.lastname: Di Rosa
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Pustorino
authors.forename: Annick
authors.initials: A
authors.lastname: Vogels
authors.forename: Ann
authors.initials: A
authors.lastname: Swillen
authors.forename: Solenn
authors.initials: S
authors.lastname: Legallic
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bou
authors.forename: Gaelle
authors.initials: G
authors.lastname: Opolczynski
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouin-Garraud
authors.forename: Marie
authors.initials: M
authors.lastname: Lemarchand
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.forename: Aude
authors.initials: A
authors.lastname: Gérard-Desplanches
authors.forename: Michèle
authors.initials: M
authors.lastname: Carlier
authors.forename: Anne
authors.initials: A
authors.lastname: Philippe
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Nolen
authors.forename: Delphine
authors.initials: D
authors.lastname: Heron
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Cyril
authors.initials: C
authors.lastname: Coizet
authors.forename: Yves
authors.initials: Y
authors.lastname: Alembik
authors.forename: Valérie
authors.initials: V
authors.lastname: Layet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Caroline
authors.initials: C
authors.lastname: Demily
authors.forename: Michel
authors.initials: M
authors.lastname: Petit
authors.forename: Florence
authors.initials: F
authors.lastname: Thibaut
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000235:genetics / Q000523:psychology*; D004827:Epilepsy / Q000097:blood / Q000201:enzymology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000097:blood / Q000201:enzymology / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D011392:Proline / Q000097:blood* / Q000235:genetics; D011394:Proline Oxidase / Q000235:genetics*; D011618:Psychotic Disorders / Q000097:blood / Q000201:enzymology / Q000235:genetics; D012307:Risk Factors
chemical_list: D011392:Proline; D008715:Methionine; D011394:Proline Oxidase; D002394:Catechol O-Methyltransferase