Abstract
Inherited 5-oxoprolinase (OPLAH) deficiency is a rare inborn condition characterised by 5-oxoprolinuria. To date, three OPLAH mutations have been described: p.H870Pfs in a homozygous state, which results in a truncated protein, was reported in two siblings, and two heterozygous missense changes, p.S323R and p.V1089I, were independently identified in two unrelated patients. We describe the clinical context of a young girl who manifested 5-oxoprolinuria together with dusky episodes and who is compound heterozygote for two novel OPLAH variations: p.G860R and p.D1241V. To gain insight into the aetiology of the 5-oxoprolinase deficiency, we investigated the pathogenicity of all the reported missense mutations in the OPLAH gene. A yeast in vivo growth assay revealed that only p.S323R, p.G860R and p.D1241V affected the activity of the enzyme.
Conclusion: Taken together, this report further suggests that hereditary 5-oxoprolinase deficiency is a benign biochemical condition caused by mutations in the OPLAH gene, which are transmitted in an autosomal recessive manner, but 5-oxoprolinuria may be a chance association in other disorders.
This is a preview of subscription content, log in via an institution to check access.
Abbreviations
- CSF:
-
Cerebrospinal fluid
- DMD:
-
Duchenne muscular dystrophy
- GC-MS:
-
Gas chromatography-mass spectrometry
- GSS:
-
Glutathione synthetase
- LP:
-
Lumbar puncture
- MAF:
-
Minor allele frequency
- OPLAH:
-
5-Oxoprolinase
- OPLAH :
-
Gene coding for 5-oxoprolinase
- OTC:
-
l-2-Oxothiazolidine-4-carboxylic acid
- PCR:
-
Polymerase chain reaction
- WT:
-
Wild-type
References
Almaghlouth I, Mohamed J, Al-Amoudi M, Al-Ahaidib L, Al-Odaib A, Alkuraya F (2012) 5-Oxoprolinase deficiency: report of the first human OPLAH mutation. Clin Genet 82:193–196
Bernier FP, Snyder FF, McLeod DR (1996) Deficiency of 5-oxoprolinase in an 8-year-old with developmental delay. J Inherit Metab Dis 19:367–368
Calpena E, Casado M, Martinez-Rubio D, Nascimento A, Colomer J, Gargallo E, Garcia-Cazorla A, Palau F, Artuch R, Espinos C (2013) 5-Oxoprolinuria in heterozygous patients for 5-oxoprolinase (OPLAH) missense changes. JIMD Rep 7:123–128
Cohen LH, Vamos E, Heinrichs C, Toppet M, Courtens W, Kumps A, Mardens Y, Carlsson B, Grillner L, Larsson A (1997) Growth failure, encephalopathy, and endocrine dysfunctions in two siblings, one with 5-oxoprolinase deficiency. Eur J Pediatr 156:935–938
Henderson MJ, Larsson A, Carlsson B, Dear PR (1993) 5-Oxoprolinuria associated with 5-oxoprolinase deficiency; further evidence that this is a benign disorder. J Inherit Metab Dis 16:1051–1052
Kumar A, Bachhawat AK (2010) OXP1/YKL215c encodes an ATP-dependent 5-oxoprolinase in Saccharomyces cerevisiae: functional characterization, domain structure and identification of actin-like ATP-binding motifs in eukaryotic 5-oxoprolinases. FEMS Yeast Res 10:394–401
Larsson A, Mattsson B, Wauters EA, van Gool JD, Duran M, Wadman SK (1981) 5-Oxoprolinuria due to hereditary 5-oxoprolinase deficiency in two brothers—a new inborn error of the gamma-glutamyl cycle. Acta Paediatr Scand 70:301–308
Mayatepek E (1999) 5-Oxoprolinuria in patients with and without defects in the gamma-glutamyl cycle. Eur J Pediatr 158:221–225
Mayatepek E, Hoffmann GF, Larsson A, Becker K, Bremer HJ (1995) 5-Oxoprolinase deficiency associated with severe psychomotor developmental delay, failure to thrive, microcephaly and microcytic anaemia. J Inherit Metab Dis 18:83–84
Pitt JJ, Hauser S (1998) Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects. Clin Chem 44:1497–1503
Ristoff E, Larsson A (2007) Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis 2:16
Roesel RA, Hommes FA, Samper L (1981) Pyroglutamic aciduria (5-oxoprolinuria) without glutathione synthetase deficiency and with decreased pyroglutamate hydrolase activity. J Inherit Metab Dis 4:89–90
Ruijter GJ, Mourad-Baars PE, Ristoff E, Onkenhout W, Poorthuis BJ (2006) Persistent 5-oxoprolinuria with normal glutathione synthase and 5-oxoprolinase activities. J Inherit Metab Dis 29:587
Schwahn B, Kameda G, Wessalowski R, Mayatepek E (2005) Severe hyperhomocysteinaemia and 5-oxoprolinuria secondary to antiproliferative and antimicrobial drug treatment. J Inherit Metab Dis 28:99–102
Acknowledgments
We thank the proband and her relatives for their kind collaboration. We are grateful to Dr. J. Evennett, Royal Derby Hospital UK, for shared care of the patient and Laura Ramírez for her technical support. C.E. has a Miguel Servet contract funded by the ISCIII and CIBERER (Grant no. CP08/00053). E.C. has a FPU grant funded by the Ministerio de Educación (Grant no. AP2009-0642). The Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative from the ISCIII. A.A.D. acknowledges receipt of a Senior Research Fellowship, from CSIR, Government of India. A.K.B. acknowledges funding through a DST-JC Bose National Fellowship. English text was revised by American Journal Experts.
Conflict of interest
The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by Beat Steinmann
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary Fig. S1
The metabolic scheme explaining the functional assay for 5-oxoprolinase. Upper panel: Activity of 5-oxoprolinase toward its natural substrate 5-oxoproline, leading to the formation of l-glutamate. Bottom panel: Activity of 5-oxoprolinase toward 2-oxothiazolidine-4-carboxylate (OTC), an analogue of 5-oxoproline, resulting in the production of l-cysteine. The l-cysteine thus generated is utilised by the S. cerevisiae met15Δ strain, an organic sulphur auxotroph leading to growth in the case of functional OPLAH and lack of growth in the case of non-functional OPLAH. (PPT 147 kb)
Supplementary Table S1
(XLSX 11 kb)
Supplementary Appendix S1
(DOC 30 kb)
Rights and permissions
About this article
Cite this article
Calpena, E., Deshpande, A.A., Yap, S. et al. New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition. Eur J Pediatr 174, 407–411 (2015). https://doi.org/10.1007/s00431-014-2397-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-014-2397-0