Genotype/phenotype correlation in patients with Erythropoietic Protoporphyria

Abstract

Homocysteine (Hcy) is a sulphur containing amino acid, derived from the metabolism of methionine. Elevated Hcy plasma concentrations result in hyperhomocysteinemia, a risk factor for cardiovascular disease. The causes are genetic defects of the key enzymes, acquired conditions, or a combination of both. In this study we assessed the effects of nitric oxide on Hcy, cysteine (Cys) and cysteinal-glycine (Cys-Gly) production by the rat hepatoma HTC cells, using the NO-donor, diethylamine NO-NOate (DEA-NO). D E A -N O caused a dose and time-dependent increase in the production of Hcy: at 500pM it caused a 3-fold increase in the levels of Hcy, Cys and Cys-Gly, whilst at 50pM increased Hcy and Cys-Gly 2.5-fold, but had no effect on Cys levels. In all experiments the NO-donor effect was apparent within 4h and maintained for 24h. Using DEA-NO, 5pM, increased production of Hcy and Cys-Gly was only observed at 4h and was indistinguishable from control levels at 24h. Experiments performed with exhausted NO-donor showed that N O -N O a t e had no effect on Hcy production indicating that the effects were due to NO alone. These results demonstrate that NO, at physiologically relevant concentrations, increase cellular Hcy production and may contribute to hyperhomocysteinemia.

Eryhtropoietic Protoporphyria

“…24 In Argentina, Parera detected three novel and two previously described mutations in five Argentinean EPP families; (1) a deletion (451delT) producing a stop codon located 18 codons downstream from the mutation, (2) IVS1-2A>G leading to exon 2 skipping, (3) IVS4-2A>G, which causes the loss of the first 48 bp of exon 5, (4) C343T, and (5) 400delA. 25 Colombo's study of 19 Argentina EPP patients identified three novel (p.S222N; p.R298X and p.R367X) and seven already known (g.12490_18067del; p.R115X; p.I186T; c.580_584delTACAG; c.598+1G>T; p.Y209X and p.W310X) and indicated the possibility of c.315-48C variant in trans to the mutated allele as a sufficient trigger of EPP. 15 In Spain, Herrero reported that three novel mutations (IVS4+1delG, 347-351delC, and 130_147dupl 18) and IVS3-48C low-expression allele in ten of 11 EPP patients.…”