Abstract
Background
Hydroxyprolinemia is an inborn error of amino acid degradation that is considered a non-disease. Known for more than 50 years, its genetic cause and prevalence have remained unclear. In MS/MS newborn screening, the mass spectrum of hydroxyproline cannot be differentiated from isoleucine and leucine causing false positive newborn screening test results for maple syrup urine disease (MSUD).
Methods
We studied two siblings with hydroxyprolinemia via exome sequencing and confirmed the candidate gene in five further individuals with hydroxyprolinemia, who were all characterized biochemically and clinically. The prevalence was calculated based on the number of individuals with hydroxyprolinemia detected via MS/MS newborn screening at our centre from 2003 to 2014.
Results
In six cases, we identified homozygous or compound heterozygous mutations in PRODH2 as the underlying genetic cause of hydroxyprolinemia. One individual was heterozygous for a deletion in PRODH2 and had an intermittent biochemical phenotype with partial normalization of hydroxyproline concentrations. In one further individual with persistent hydroxyprolinemia no mutation in PRODH2 was found, raising the possibility of another defect of hydroxyproline degradation yet to be identified as the underlying cause of hydroxyprolinemia. Plasma hydroxyproline concentrations were clearly elevated in all individuals with biallelic mutations in PRODH2. All studied individuals remained asymptomatic, giving further evidence that hydroxyprolinemia is a benign condition. The estimated prevalence of hydroxyprolinemia in Germany is about one in 47,300 newborns.
Conclusion
Our results establish mutations in PRODH2 as a cause of human hydroxyprolinemia via impaired dehydrogenation of hydroxyproline to delta1-pyroline-3-hydroxy-5-carboxylic acid, and we suggest PRODH2 be renamed HYPDH. Hydroxyprolinemia is an autosomal-recessively inherited benign condition. It is a frequent cause of false positive screening results for MSUD, the prevalence being about 2.5 times higher than that of MSUD.
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Acknowledgments
We thank the affected individuals and their families for participation in the study.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients or their parents in the case of minor patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article. This article does not contain any studies with animal subjects performed by any of the authors.
Funding
This study was generously funded by the Dietmar Hopp Foundation, St. Leon-Rot, Germany. The study was further supported by the Bundesministerium für Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET, 01GM1113C to H.P.), through the E-Rare project GENOMIT (01GM1207 for H.P.) and the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C for T.B.H.).
Web resources
The URLs for data presented herein are as follows:
MutationTaster, http://www.mutationtaster.org
NHLBI Exome Sequencing Project Exome Variant Server, http://evs.gs.washington.edu/EVS
ExAC, http://exac.broadinstitute.org
Online Mendelian Inheritance in Man (OMIM), http://www.omim.org
PolyPhen-2, http://genetics.bwh.harvard.edu/pph2
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Communicated by: Eva Morava
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Staufner, C., Haack, T.B., Feyh, P. et al. Genetic cause and prevalence of hydroxyprolinemia. J Inherit Metab Dis 39, 625–632 (2016). https://doi.org/10.1007/s10545-016-9940-2
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DOI: https://doi.org/10.1007/s10545-016-9940-2