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Type I hyperprolinemia: genotype/phenotype correlations
Author(s) -
Guilmatre Audrey,
Legallic Solenn,
Steel Gary,
Willis Alecia,
Di Rosa Gabriella,
Goldenberg Alice,
DrouinGarraud Valérie,
Guet Agnès,
Mignot Cyril,
Des Portes Vincent,
Valayannopoulos Vassili,
Van Maldergem Lionel,
Hoffman Jodi D.,
Izzi Claudia,
EspilTaris 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
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21296
Subject(s) - biology , proline dehydrogenase , allele , genotype , genetics , missense mutation , haplotype , allele frequency , phenotype , gene , mutation , microbiology and biotechnology , proline , amino acid
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. © 2010 Wiley‐Liss, Inc.