Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia

Abstract

We surveyed Delta1-pyrroline 5-carboxylate dehydrogenase genes from four patients with hyperprolinemia type II using RT-PCR amplification, genomic PCR amplification and direct sequencing. We found four mutant alleles, two with frameshift mutations [A7fs(-1) and G521fs(+1)] and two with missense mutations (S352L and P16L). To test the functional consequences of three of these, we expressed them in a P5CDh-deficient strain of Saccharomyces cerevisiae . In contrast to wild-type human P5CDh, yeast expressing S352L and G521fs(+1) failed to grow on proline and had no detectable P5CDh activity. The P16L allele, however, produced fully functional P5CDh and subsequent analysis suggests that it is polymorphic in the relevant (Spanish) population. Interestingly, the G521fs(+1) allele segregates in the large Irish Traveller pedigree used to define the HPII phenotype. To our knowledge, this is the first description of the molecular basis for this inborn error.

Substrate specificity, plasma membrane localization, and lipid modification of the aldehyde dehydrogenase ALDH3B1

“…Aldehydes and their associated toxicity are implicated in various disorders, including cataract, cutaneous disorder, cancer, neuronal diseases, alcoholic liver disease, and male infertility [1][2][3][4][35][36][37][38].…”

“…There are 19 ALDHs known in humans with different substrate specificity, tissue distribution, and intracellular localization [1]. Mutations in these ALDH genes and consequent aldehyde accumulation have been implicated in the pathogenesis of several inherited diseases, including Sjögren-Larsson syndrome (ALDH3A2) [2], type II hyperprolinemia (ALDH4A1) [3], pyridoxine-dependent seizures (ALDH7A1) [4], and -hydroxybutyric aciduria (ALDH5A1) [5].…”

The Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase in Proline Degradation[W]

“…Consistently, yeast strains deficient in P5CDH were hypersensitive to Pro (Deuschle et al, 2001;Nomura and Takagi, 2004). In humans, defects in HsP5CDH result in type 2 hyperprolinemia, with patients experiencing seizures and variable degrees of mental retardation (Geraghty et al, 1998;Morita et al, 2002). Furthermore, both overexpression of ProDH or P5C treatment (400 mM) induced apoptosis in human tumor cell lines (Maxwell and Davis, 2000), and Donald et al (2001) reported ProDHdependent formation of reactive oxygen species (ROS) in human cells and induction of apoptosis.…”

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion of Trypanosoma cruzi

“…In CHO-K 1 cells, P5C was shown to be involved in redox metabolism by up-regulating the hexose monophosphate shunt pathway (33). Farrant et al (35) assessed the response of patients with P5CDH deficiency, which was previously reported as an inborn error of metabolism (hyperprolinemia type II), and showed that an increased intracellular P5C pool chemically inhibits vitamin B 6 (pyridoxal 5Ј-phosphate) (34), which is an essential prosthetic group of transaminases. Taken together, these data suggest that the proline-glutamate interconversion pathway participates in relevant physiological processes and that the altered equilibrium of their components might elicit detrimental effects beginning at the mitochondrial level and leading to cell death.…”