The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene

Abstract

: type I (MIM 239500) results from the defect of the enzyme proline dehydrogenase (oxidase), which ensures the conversion of proline into ∆-1-pyrroline-5-carboxylate (P5C), the first step in the conversion from proline to glutamate, 4 and type II (MIM 239510) is the result of a defect of the P5C dehydrogenase/aldehyde dehydrogenase 4 enzyme and P5C is excreted in the urine. 5The phenotype of type II hyperprolinaemia is characterised by neurological manifestations including seizures and mental retardation.3 6 7 Although type I hyperprolinaemia was originally described in a kindred with a familial nephropathy, 1 2 the renal disease was subsequently shown to be coincidental and type I hyperprolinaemia has been considered to be a benign disorder which can be asymptomatic.3 Nevertheless, two studies have reported severe neurological manifestations (mental retardation, epilepsy) in two male children with type I hyperprolinaemia.8 9 While mutations of the ALDH4A1 gene, located on chromosome 1p36, have been identified in families with type II hyperprolinaemia, 10 the molecular basis of type I hyperprolinaemia has not been characterised until recently. We have recently identified in schizophrenic patients a heterozygous deletion and mutations of the PRODH gene, located on 22q11, which were associated with moderate hyperprolinaemia. We also found in two unrelated type I hyperprolinaemia children the same homozygous PRODH missense mutation.11 We now report the identification of a complete homozygous PRODH deletion in a child with type I hyperprolinaemia with severe neurological manifestations. CASE REPORTThe patient, a male, was the first child of healthy, consanguineous parents of Egyptian origin. At 4 years, he was referred for severe psychomotor delay, permanent hyperactivity, sleep disturbance with bruxism, and status epilepticus. Weight was 13 kg (−3 SD), length 95 cm (−2.5 SD), and head circumference 46 cm (−4 SD). There was no dysmorphism. Cerebral magnetic resonance imaging (MRI), performed at 4 years of age, showed normal myelination and no white matter abnormalities. Metabolic screening showed a very high level of plasma proline level (2246 µmol/l, n=133-227 µmol/l). Proline levels were also raised in urine (631 µmol/mmol creatinine, n<10 µmol/mmol creatinine) and cerebrospinal fluid (21 µmol/l, Key points• Type I hyperprolinaemia (MIM 239500) is a rare metabolic disorder which is biochemically characterised by a defect of the proline dehydrogenase (oxidase) enzyme involved in the conversion from proline to glutamate. Although type I hyperprolinaemia has been considered to be a benign disorder, severe neurological manifestations (mental retardation, epilepsy) have been reported in several affected subjects.• We identified, in a child with a severe form of type I hyperprolinaemia with severe psychomotor delay and status epilepticus associated with a very high level of plasma proline level (2246 µmol/l), a complete homozygous deletion of the PRODH gene located on chromosome 22q11. This 22q11 deletion, also removing...

Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress

“…At 0.5 mM proline in the external medium proline, survival of HEK 293 cells increased to 65%. The concentration of proline in human plasma is normally around 0.2 -0.3 mM and in type I hyperprolinaemia plasma proline levels have been reported up to 2.2 mM [37]. Therefore, proline concentrations in the medium at which protection against H 2 O 2 is observed are near physiological levels.…”

Hyperprolinemia is a risk factor for schizoaffective disorder

“…The estimated size of the PRODH deletion, approximately 350 kb, was identical in the two unrelated patients and was similar to that previously identified, in the homozygous state, in a patient suffering from a severe form of type I hyperprolinemia. 7 The frequency of the detected PRODH variations was then assessed in the whole sample including patients and controls. As shown in Table 4, the allele frequencies, except in one case, significantly differed between hyperprolinemic and nonhyperprolinemic subjects.…”

“…6 Interestingly, we subsequently found the same PRODH deletion and the L441P substitution at the homozygous state in children suffering from a severe form of type I hyperprolinemia, a condition characterized by high plasma proline levels, seizures and mental retardation. 7 To determine whether the association between hyperprolinemia and psychosis was circumstantial or whether mild to moderate hyperprolinemia is indeed a risk factor for psychotic illness, we undertook a large case-control study including 434 subjects (114 …”

Schizophrenia genetics: uncovering positional candidate genes

“…20 In addition to being one of the most variable genes in the human genome, the PRODH gene is haploinsufficient: heterozygous deletions of PRODH and the presence of heterozygous mutations of the PRODH gene are associated with moderate hyperprolinemia (300 -600 mmol/l). 20,21 As a result of the hemizygous nature of the 22q11 microdeletions, haploinsufficiency (gene dosage-dependence) is likely to be an important property of any gene that modulates the emergence of the 22q11 psychiatric phenotypes, as it was the case for Tbx1, a gene that modulates in a dosage-dependent manner the cardiac features associated with these microdeletions. 22 A mutation in the mouse ortholog of the human PRODH gene in the Pro/Re hyperprolinemic mouse strain has been described.…”