5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

Abstract

The inherited 5-oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione (GSH) metabolism: the glutathione synthetase (GSS) and the 5-oxoprolinase (OPLAH). The GSS deficiency is the best characterized of the inborn errors of GSH metabolism, whereas the OPLAH deficiency is questioned whether it is a disorder or just a biochemical condition with no adverse clinical effects. Recently, the first human OPLAH mutation (p.H870Pfs) was reported in homozygosis in two siblings who suffered from 5-oxoprolinuria with a benign clinical course. We report two unrelated patients who manifested massive excretion of 5-oxoproline in urine. In both probands, the blood GSH levels were normal and no mutations were found in the GSS gene. The mutational screening of the OPLAH gene, which included the codified sequences, the intronic flanking sequences, the promoter sequence, and a genetic analysis in order to detect large deletions and/or duplications, showed that each patient only harbors one missense mutation in heterozygosis. The in silico analyses revealed that each one of these OPLAH mutations, p.S323R and p.V1089I, could alter the proper function of this homodimeric enzyme. In addition, clinical symptoms manifest in these two probands were not related to GSH cycle defects and, therefore, this study provides further evidence that oxoprolinuria may present as epiphenomenon in several pathological conditions and confound the final diagnosis.

Emerging Regulatory Paradigms in Glutathione Metabolism

“…This led to the suggestion that the conversion of γ-glutamylcysteine to 5-oxoproline and cysteine by GGCT may be the major source of 5-oxoproline (Oakley et al, 2008). However, there are examples of patients that present with 5-oxoprolinuria who have normal circulating glutathione concentrations despite increased 5-oxoproline levels (Calpena et al, 2013). These levels show glutathione homeostasis is normal in these patients.…”

Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies

“…In 2013, c.959C>A (p.S323R) heterozygous mutation was identified in a 1-year-old girl. c.3265G>A (p.V1089I) heterozygous mutation (SNP rs185836803) was detected in an 8-year-old boy with 5- oxoprolinuria combined with Duchenne muscular dystrophy [3]. In 2014, c.2578G>A (p.G860R) and c.3722A>T (p.D1241V) compound heterozygous mutations were detected in a young girl presenting with 5-oxoprolinuria and dusky episodes [4].…”

“…OPLAH gene is located on chromosome 8q24.3, including at least 26 exons [16]. Five mutations have been reported till now [2][3][4]. In 2012, c.2601_2602insC (p.H870Pfs * 92) mutation was identified from a 10-year-old boy.…”

“…The first domain, which acts as the actin-like ATPase domain, contains three crucial ATP-binding sites. The second domain is not well understood, but the homodimeric structure may allow some mutations to be tolerated without drastically altering the phenotype [3].…”

“…5-Oxoprolinase deficiency is a very rare autosomal recessive disorder caused by mutations in the OPLAH gene (OMIM 614243). Only very few cases of 5-oxoprolinase deficiency have been documented worldwide [2][3][4]. The patients present with a number of clinical symptoms including mental retardation, enterocolitis, hypoglycemia, microcytic anemia, microcephaly and renal stones [5].…”