Type I hyperprolinemia: genotype/phenotype correlations

Audrey Guilmatre (1, 2) , Solenn Legallic (1) , Gary Steel (3) , Alecia Willis (3) , Gabriella Di Rosa (4) , Alice Goldenberg (5) , Valérie Drouin-Garraud (5) , Agnès Guet (6) , Cyril Mignot (6) , Vincent Des Portes (7, 8) , Vassili Valayannopoulos (9) , Lionel van Maldergem (10) , Jodi D Hoffman (11) , Claudia Izzi (12) , Caroline Espil-Taris (13) , Simona Orcesi (14) , Luisa Bonafé (15) , Eric Le Galloudec (16) , Hélène Maurey (17) , Christine Ioos (18) , Alexandra Afenjar (19) , Patricia Blanchet (20) , Bernard Echenne (21) , Agathe Roubertie (22) , Thierry Frebourg (1, 5) , David Valle (3) , Dominique Campion (1, 2)

1 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
2 Estonian Genome and Medicine
3 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
4 Department of Medical and Surgical Pediatrics
5 Department of Genetics
6 CHU Trousseau [APHP]
7 L2C2 - Laboratoire sur le langage, le cerveau et la cognition
8 University Hospital
9 Department of Neuro-Metabolism
10 Regional Hospital
11 Tufts Medical Center
12 UniBs - Università degli Studi di Brescia = University of Brescia
13 University Hospital
14 Fondation "Neurological Institute C. Mondino "
15 UNIL - Université de Lausanne = University of Lausanne
16 Beauvais Hospital
17 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
18 Raymond-Poincaré Hospital
19 CHU Pitié-Salpêtrière [AP-HP]
20 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
21 Hôpital Gui de Chauliac [CHU Montpellier]
22 Service de neuropédiatrie

Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. 8/14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for 6 novel mutations and 2 haplotypes. The c.1331G>A, p.G444D allele has a drastic effect whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity <50%. 8 out of 9 subjects with a predicted residual activity ≥50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

Mots clés: Life Sciences

Domaines: Neurosciences

Audrey Guilmatre, Solenn Legallic, Gary Steel, Alecia Willis, Gabriella Di Rosa, et al.. Type I hyperprolinemia: genotype/phenotype correlations. Human Mutation, 2010, 31 (8), pp.961-965. ⟨10.1002/humu.21296⟩. ⟨hal-00599468⟩