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Human Molecular Genetics Advance Access originally published online on November 29, 2006
Human Molecular Genetics 2007 16(1):83-91; doi:10.1093/hmg/ddl443
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome

Grégory Raux1, Emilie Bumsel1, Bernadette Hecketsweiler2, Therese van Amelsvoort3, Janneke Zinkstok3, Sylvie Manouvrier-Hanu4, Carole Fantini4, Georges-Marie M. Brévière5, Gabriella Di Rosa6, Giuseppina Pustorino6, Annick Vogels7, Ann Swillen7, Solenn Legallic1, Jacqueline Bou1, Gaelle Opolczynski8, Valérie Drouin-Garraud1, Marie Lemarchand1, Nicole Philip9, Aude Gérard-Desplanches10, Michèle Carlier11, Anne Philippe12, Marie Christine Nolen12, Delphine Heron13, Pierre Sarda14, Didier Lacombe15, Cyril Coizet15, Yves Alembik16, Valérie Layet17, Alexandra Afenjar18, Didier Hannequin1, Caroline Demily1,8, Michel Petit1,8, Florence Thibaut1,8, Thierry Frebourg1 and Dominique Campion1,8,*

1 Department of Genetics and Inserm U614, IFRMP, Faculty of Medicine, Rouen, France, 2 Laboratory of Biochemistry, CHRU, Rouen, France, 3 Department of Psychiatry, AMC, Amsterdam, The Netherlands, 4 Department of Genetics and 5 Department of Cardio-Pediatrics, CHRU, Lille, France, 6 Department of Medical and Surgical Pediatrics, Unit of Infantile Neuropsychiatry, University Hospital, Messina, Italy, 7 Center for Human Genetics, University Hospital, Leuven, Belgium, 8 Units of Psychiatry, CH du Rouvray and CHRU, Rouen, France, 9 Department of Genetics, CHRU Marseille, France, 10 Research Center PsyCLE (EA3273) and 11 Cognitive Psychology UMR 6146 CNRS, Aix Marseille 1 University, France, 12 INSERM U781 and Department of Genetics, Hôpital Necker-enfants malades, Paris, France, 13 Department of Genetics, Hôpital Pitié Salpétrière, Paris, France, 14 Department of Genetics, CHRU Montpellier, France, 15 Department of Genetics, CHRU Bordeaux, France, 16 Department of Genetics, CHRU Strasbourg, France, 17 Department of Genetics, CHR Le Havre, France and 18 Department of Neuropediatry, Hopital Trousseau, Paris, France

* To whom correspondence should be addressed at: Inserm U614, Faculté de Médecine, 22 bd Gambetta, 76183 Rouen, France. Tel: +33 235148280; Fax: +33 235148237; Email: dominique.campion{at}univ-rouen.fr

Received September 28, 2006; Accepted November 16, 2006

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.


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