ABSTRACT
BACKGROUND: Acute Hepatic Porphyrias (AHPs) are characterized by an acute neuroabdominal syndrome including both neuropsychiatric symptoms and neurodegenerative changes. Two main hypotheses explain the pathogenesis of nervous system dysfunction: (a) the ROS generation by autooxidation of 5-aminolevulinic acid accumulated in liver and brain; (b) liver heme deficiency and in neural tissues that generate an oxidative status, a component of the neurodegenerative process. METHODS: We review results obtained from Acute Intermittent Porphyria (AIP) and Variegate Porphyria (VP) families studied at clinical, biochemical, and molecular level at the CIPYP in Argentina. The relationship between the porphyric attack and oxidative stress was also evaluated in AHP patients and controls, to identify a marker of neurological dysfunction. RESULTS: We studied 116 AIP families and 30 VP families, 609 and 132 individuals, respectively. Genotype/phenotype relation was studied. Oxidative stress parameters and plasma homocysteine levels were measured in 20 healthy volunteers, 22 AIP and 12 VP individuals. CONCLUSION: No significant difference in oxidative stress parameters and homocysteine levels between the analyzed groups were found.
Subject(s)
Mutation , Oxidative Stress , Porphyrias, Hepatic/genetics , Argentina , Female , Heme/metabolism , Homocysteine/blood , Humans , Male , Porphyrias, Hepatic/blood , Porphyrias, Hepatic/pathologyABSTRACT
Porphyrias are a group of metabolic diseases that affect the skin and/or nervous system. In 2008, three unrelated patients were diagnosed with variegate porphyria at the CIPYP (Centro de Investigaciones sobre Porfirinas y Porfirias). Sequencing of the protoporphyrinogen oxidase gene, the gene altered in this type of porphyria, revealed three previously undescribed mutations: c.338+3insT, c.807G>A, and c.808-1G>C. As these mutations do not affect the protein sequence, we hypothesized that they might be splicing mutations. RT-PCRs performed on the patient's mRNAs showed normal mRNA or no amplification at all. This result indicated that the aberrant spliced transcript is possibly being degraded. In order to establish whether they were responsible or not for the patient's disease by causing aberrant splicing, we utilized a minigene approach. We found that the three mutations lead to exon skipping; therefore, the abnormal mRNAs are most likely degraded by a mechanism such as nonsense-mediated decay. In conclusion, these mutations are responsible for the disease because they alter the normal splicing pathway, thus providing a functional explanation for the appearance of disease and highlighting the use of minigene assays to complement transcript analysis.
ABSTRACT
BACKGROUND/AIMS: The porphyrias are genetically heterogeneous diseases, and each mutation is exclusive to one or two families. Among the mutations responsible for variegate porphyria in our country, c.1042_1043insT stands out, since it was described only in Argentina and is present in about 40% of genetically diagnosed families. Thus, we hypothesized the possible existence of a common ancestor for the mutation in our population. METHODS: We conducted a study based on microsatellite (short tandem repeats) haplotypes. RESULTS: We found a common haplotype in all of the patients carrying the common mutation. The age of the mutation was estimated to be about 375 years. CONCLUSION: There is a recent founder effect in our population for this particular genetic alteration in variegate porphyria.
