PubMed Health⌕ Search

Biomedical subjects

A De Siervi

Publications and source records attributed to A De Siervi.

9 recordsLinked to original sources
PubMed2003

Acute porphyrias in the Argentinean population: a review.

The porphyrias are a group of inherited metabolic disorders of heme biosynthesis which result from a partial deficiency in one of its seven specific enzymes, after its first and rate limiting enzyme, delta-aminolevulinic acid synthetase. They can be classified on the basis of their clinical manifestations into cutaneous, acute and mixed disorders. Acute intermittent porphyria (AIP) is the most common type of hepatic acute porphyrias, inherited as an autosomal dominant trait, caused by a defect in the gene which codifies for the heme enzyme porphobilinogen deaminase. Its prevalence in the Argentinean population is about 1:125,000. A partial deficiency in another enzyme, protoporphyrinogen oxidase, produces variegate porphyria (VP), the second acute porphyria most frequent in the Argentinean population (1:600,000). Here, we review all the mutations we have found in 46 AIP and 9 VP unrelated Argentinean patients. To screen for mutations in symptomatic patients, we have proposed a geneticresearch strategy.

Argentina↗
PubMed2000

Mutations in familial porphyria cutanea tarda: two novel and two previously described for hepatoerythropoietic porphyria.

Uroporphyrinogen decarboxylase (URO-D) deficiency is responsible for two forms of genetic cutaneous porphyria: familial porphyria cutanea tarda (f-PCT) and hepatoerythropoietic porphyria (HEP). The f-PCT transmitted as an autosomal dominant trait, is characterized by photosensitive cutaneous lesions frequently associated to hepatic dysfunction and is precipitated by various ecogenic factors. The HEP, transmitted as a recessive trait, is more severe than f-PCT and would be considered as the homozygous form of f-PCT. For the mutational analysis of f-PCT patients, the entire URO-D gene was amplified and each exon, intron-exon boundaries and the promoter region were cycle sequenced. Five mutations were found in 6 unrelated families studied, of these, two were new: a nonsense mutation in exon 6 (W159X) and a splice defect in intron 9 (IVS9(-1)G-->C). The other two missense mutations, P62L and A80G, had been previously reported in the homozygous state in HEP families. The g10insA, reported in our laboratory, was again identified in other two unrelated families. In addition 3 novel URO-D polymorphisms in non-coding regions were found. The reverse transcription-PCR and sequencing of the splice mutation carrier's RNA did not reveal the presence of an abnormal mRNA, suggesting that no stable transcript from the mutated allele is synthesized. These results increase to 39 the number of mutations identified in the URO-D gene; 4 of them causing both HEP and f-PCT.

Adult↗
PubMed2000

Identification and characterization of two novel mutations that produce acute intermittent porphyria: A 3-base deletion (841-843delGGA) and a missense mutation (T35M).

A partial deficiency of Porphobilinogen deaminase (PBGD) is responsible for acute intermittent porphyria (AIP). AIP is inherited in an autosomal dominant fashion, and the prevalence in the Argentinean population is about 1:125,000. Here, two new mutations and two previously reported were found in the PBGD gene in 22 Argentinean AIP patients corresponding to 8 different families. To screen for AIP mutations in symptomatic patients, genomic DNA isolated was amplified in 6 PCR reactions, then all coding exons and flanking intronic regions were sequenced. The novel mutations are 841-843delGGA in exon 14, which results in the loss of glycine-281 (G281del), and one 104C>T point mutation in the exon 4 (T35M). To further characterize both novel mutations, the pKK-PBGD construct for the mutant alleles were expressed in E. coli, the enzymatic activity of the recombinant proteins were 1% and 4% of the mean level expressed by the normal allele for 841-843delGGA and T35M, respectively. Hum Mutat 16:373, 2000.

Adolescent↗
PubMed1999

Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation.

Acute intermittent porphyria (AIP), the most common hepatic porphyria, results from the half-normal activity of hydroxymethylbilane synthase (HMB-synthase; EC 4.3.1.8), the third enzyme in the heme biosynthetic pathway. Because life-threatening acute neurologic attacks of this autosomal dominant disease are triggered by various ecogenic factors (e.g., certain drugs, hormones, alcohol, and starvation), efforts have been directed to identify and counsel presymptomatic heterozygotes in affected families to avoid the precipitating factors. Thus, to determine the nature of the mutations causing AIP in 26 unrelated enzyme-confirmed patients from Argentina, a long-range polymerase chain reaction method was developed to amplify the entire 10-kb gene in two fragments for efficient cycle sequencing and mutation detection. Eight new mutations were identified including two missense mutations (Q34P and G335S), four small deletions (728delCT, 815delAGGA, 948delA, and 985del12), a single base insertion (666insA), and a splice site mutation (IVS12(+1)). In addition, five previously reported mutations (G111R, R173W, Q204X, R201W, and 913insC) were detected. Notably, G111R was identified in 12 of the 26 (46%) presumably unrelated propositi; however, haplotype analysis with intragenic and flanking markers indicated an ancestral founder. Expression of the two new missense mutations (Q34P and G335S) in f1 E. coli resulted in 2.5% or less of the normal expressed enzyme, confirming their defective function. Thus, eight new and five previously reported HMB-synthase mutations, including a common lesion, were detected, permitting accurate identification and counseling of presymptomatic carriers in these 26 unrelated Argentinean AIP families with this dominant porphyria.

Adolescent↗
PubMed1999

Acute intermittent porphyria: characterization of two novel mutations in the porphobilinogen deaminase gene, one amino acid deletion (453-455delAGC) and one splicing aceptor site mutation (IVS8-1G>T).

A partial deficiency of Porphobilinogen deaminase (PBG-D) is responsible for acute intermittent porphyria (AIP). AIP is inherited in an autosomal dominant fashion, and the prevalence in the Argentinean population is about 1:125,000. Here, two new mutations and three previously reported were found in the PBG-D gene in 12 Argentinean AIP patients corresponding to 5 different families. To screen for AIP mutations in symptomatic patients, genomic DNA isolated was amplified in 2 Multiplex PCR reactions, then all coding exons and flanking intronic regions were sequenced. The new mutations are 453-455delAGC in exon 9 which results in the loss of an alanine residue at position 152, and one new point mutation in the splicing aceptor site in the last position of intron 8 (IVS8-1G>T) which leds to a 15 bp deletion because a cryptic site (first AG upstream) is used. Both mutations produce amino acid deletion without frameshift effect. To further characterize the 453-455delAGC mutation, the pKK-PBGD construct for the mutant allele was expressed in E. coli, the enzymatic activity of the recombinant protein was 1.3% of the mean level expressed by the normal allele. Finally, three missense mutations, previously reported, were identified in three unrelated families.

Adolescent↗
PubMed1999

Acute intermittent porphyria: biochemical and clinical analysis in the Argentinean population.

Acute intermittent porphyria (AIP) is the most common type of hepatic acute porphyria. In this work, we have analyzed the biochemical data of all Argentinean AIP families studied in the Porphyrins and Porphyrias Research Centre (CIPYP). We have shown that: (i) the prevalence for this population is about 1:125,000; (ii) the disease is more frequent in women than in men (7:3); (iii) about 60% are latent carriers; (iv) 15% of patients with symptomatic AIP died during an acute attack; (v) the most important precipitating factors of acute attacks in our population were the ingestion of therapeutic drugs (25%), anesthetics in surgical interventions (25%) and infections (20%); (vi) the initial symptom in Argentinean AIP individuals is severe abdominal pain (100%), and it is often accompanied by constipation (37%), anorexia (37%) and tachycardia (30%); and (vii) the percentage of recurrence of the acute attacks is high (81%).

Adult↗
PubMed1996

Porphyrin biosynthesis in normal and haem mutants of Saccharomyces cerevisiae. Studies on the inheritance of the HEM R+ phenotype.

Heme biosynthesis was studied in the segregants of Saccharomyces cerevisiae (DW10 tetrade 2) from D27 and D27/C6 mating, as a function of the carbon source in the growth medium and the physiological state of the cells. The effects of the HEM R+ gene on the 5-aminolevulinate synthase (ALA-S) and 5-aminolevulinate dehydratase (ALA-D) activities of heme biosynthesis in cells grown on nonfermentable and fermentable carbon sources were compared. Profiles obtained for both strains grown on a fermentable carbon source (glucose) were identical. However, in the presence of a nonfermentable carbon source (ethanol), they behave quite different, as if the mutation could only be expressed under these growth conditions. Moreover, their behavior is similar to that found for the parental strains, indicating that for the mutant its particular behavior might be inheritedly linked to the HEM R+ gene, which in turn affects some regulatory aspects of ALA synthesis explaining its characteristic phenotype.

5-Aminolevulinate Synthetase↗