Type I hyperprolinemia: genotype/phenotype correlations

• Published in: Human mutation Vol. 31; no. 8; pp. 961 - 965
• Main Authors: Guilmatre, Audrey, Legallic, Solenn, Steel, Gary, Willis, Alecia, Di Rosa, Gabriella, Goldenberg, Alice, Drouin-Garraud, Valérie, Guet, Agnès, Mignot, Cyril, Des Portes, Vincent, Valayannopoulos, Vassili, Van Maldergem, Lionel, Hoffman, Jodi D, Izzi, Claudia, Espil-Taris, Caroline, Orcesi, Simona, Bonafé, Luisa, Le Galloudec, Eric, Maurey, Hélène, Ioos, Christine, Afenjar, Alexandra, Blanchet, Patricia, Echenne, Bernard, Roubertie, Agathe, Frebourg, Thierry, Valle, David, Campion, Dominique
• Format: Journal Article Web Resource
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2010; John Wiley & Sons, Inc; Wiley; Wiley Liss
• Subjects: 22q11; Adolescent; Adult; Alleles; Amino Acid Metabolism, Inborn Errors - enzymology; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors/enzymology/genetics; Case-Control Studies; Child; Child, Preschool; Cognitive science; Female; Genetic Association Studies; Genetics & genetic processes; Genotype & phenotype; Génétique & processus génétiques; Humans; Infant; Life sciences; Male; Mutation; Mutation, Missense - genetics; Neuroscience; POX enzymatic activity; PRODH; Proline - metabolism; Proline Oxidase - genetics; Sciences du vivant; type I hyperprolinemia; Life Sciences
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21296

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. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two 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%. Eight out of nine 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. Hum Mutat 31:961-965, 2010.