Genetic analysis of Variegate Porphyria (VP) in Italy: Identification of six novel mutations in the protoporphyrinogen oxidase (PPOX) gene

D’Amato, Mauro; Bonuglia, Margherita; Barile, Simona N.; Griso, D.; Macrí, A.; Biolcati, G.

doi:10.1002/humu.9125

Cited by 4 publications

(5 citation statements)

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“…In other two families, 2 previously described mutations were found. One was a missense mutation, G232R in exon 7 (Table 1 , Proband XI), already published by Deybach et al [ 35 ] and D'Amato et al [ 36 ]. The other was the insertion 1082insC in exon 10 (Table 1 , Proband XII) which results in a frameshift at aminoacid 359 with a premature stop codon 18 codons downstream (p.S359fsX377), so introducing 18 novel amino acids [ 37 - 39 ].…”

Section: Resultsmentioning

confidence: 98%

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Genetic and biochemical studies in Argentinean patients with variegate porphyria

et al. 2008

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BackgroundA partial deficiency in Protoporphyrinogen oxidase (PPOX) produces the mixed disorder Variegate Porphyria (VP), the second acute porphyria more frequent in Argentina. Identification of patients with an overt VP is absolutely important because treatment depends on an accurate diagnosis but more critical is the identification of asymptomatic relatives to avoid acute attacks which may progress to death.MethodsWe have studied at molecular level 18 new Argentinean patients biochemically diagnosed as VP. PPOX gene was amplified in one or in twelve PCR reactions. All coding exons, flanking intronic and promoter regions were manual or automatically sequenced. For RT-PCR studies RNA was retrotranscripted, amplified and sequenced. PPOX activity in those families carrying a new and uncharacterized mutation was performed.ResultsAll affected individuals harboured mutations in heterozygous state. Nine novel mutations and 3 already reported mutations were identified. Six of the novel mutations were single nucleotide substitutions, 2 were small deletions and one a small insertion. Three single nucleotide substitutions and the insertion were at exon-intron boundaries. Two of the single nucleotide substitutions, c.471G>A and c.807G>A and the insertion (c.388+3insT) were close to the splice donor sites in exons 5, 7 and intron 4 respectively. The other single nucleotide substitution was a transversion in the last base of intron 7, g.3912G>C (c.808-1G>C) so altering the consensus acceptor splice site. However, only in the first case the abnormal band showing the skipping of exon 5 was detected. The other single nucleotide substitutions were transversions: c.101A>T, c.995G>C and c.670 T>G that result in p.E34V, p.G332A and W224G aminoacid substitutions in exons 3, 10 and 7 respectively. Activity measurements indicate that these mutations reduced about 50% PPOX activity and also that they co-segregate with this reduced activity value. Two frameshift mutations, c.133delT and c.925delA, were detected in exons 3 and 9 respectively. The first leads to an early termination signal 22 codons downstream (p.S45fsX67) and the second leads to a stop codon 5 codons downstream (p.I309fsX314). One reported mutation was a missense mutation (p.G232R) and 2 were frameshift mutations: c.1082insC and 1043insT. The last mutation was detected in six new apparently unrelated Argentinean families.ConclusionMolecular analysis in available family members revealed 14 individuals who were silent carriers of VP. Molecular techniques represent the most accurate approach to identify unaffected carriers and to provide accurate genetic counselling for asymptomatic individuals. The initial screening includes the insertion search.

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Section: Resultsmentioning

confidence: 98%

“…The other 2 reported mutations were frameshift mutations. One of them was a C insertion in the streach of 6 Cs in exon 10 (c.1077-1082insC), which had been previously described by D'Amato et al [ 36 ] and Whatley et al [ 37 ]. This same mutation was recently described for the Swiss [ 38 ] and Spanish [ 39 ] populations.…”

Section: Discussionmentioning

confidence: 95%

Genetic and biochemical studies in Argentinean patients with variegate porphyria

et al. 2008

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“…Variegate porphyria is rare, with a reported prevalence of 0.5–2 per 100,000 but more common in South Africa, affecting 1 in 300 people due to a founder effect . VP usually presents between 20 and 40 years of age.…”

Section: Acute Hepatic Porphyriasmentioning

confidence: 99%

“…Because PPO deficiency decreases levels of heme, hepatic ALA synthase is upregulated, such that porphyrins and other heme precursors accumulate in the liver and disperse throughout the body . Deposition predisposes to cutaneous symptoms and acute neurologic attacks . Factors that induce the cytochrome p450 system increase the demand for heme and can trigger an attack …”

Section: Acute Hepatic Porphyriasmentioning

confidence: 99%

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Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology

et al. 2013

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The porphyrias are a group of disorders characterized by defects in the heme biosynthesis pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis, and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes, anemia, and liver disease. With advances in DNA analysis, researchers are discovering the underlying genetic causes of the porphyrias, enabling family members to be tested for genetic mutations. Here we present a comprehensive review of porphyria focusing on those with cutaneous manifestations. In Part I, we have included the epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Treatment and management options will be discussed in Part II. IntroductionThe porphyrias are a group of disorders characterized by defects in heme production, resulting in buildup of toxic heme precursors (Table 1). Cutaneous findings are common and include photosensitivity, painful burning, bullae, and scarring. Diagnosis requires laboratory measurement of heme precursors in plasma, urine, stool, and erythrocytes.Heme is made from glycine and succinyl-coenzyme A in eight steps (Fig. 1). Heme synthesis is ubiquitous throughout the body, but 85% occurs in bone marrow, becoming hemoglobin.1 Porphyrias are classified into two categories based on whether heme precursors build up in the liver (hepatic porphyrias) or bone marrow (erythropoietic porphyrias). Hepatic porphyrias are subdivided into acute and chronic subtypes, and tend to have secondary triggers (e.g., drugs, alcohol, hormone fluctuation, infection, and fasting). Acute hepatic porphyrias present with episodes (acute attacks) of abdominal or neurological symptoms caused by a genetic predisposition with a secondary metabolic trigger. Porphyria cutanea tarda (PCT), the only chronic hepatic porphyria, has a prolonged course of liver damage and photosensitivity. Erythropoietic porphyrias present in childhood with photosensitivity. While the main defect lies in the erythrocytes, the liver may also be involved. Materials and methodsA comprehensive literature search was initially performed using PubMed. Broad searches were performed using the terms "porphyria," "coproporphyria," and "protoporphyria" in the title, and "skin diseases, genetic" in the medical subject heading, but excluding for medical subject heading "acute intermittent." Articles

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Porphyrien

Frank

2016

Hautarzt

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Genetic analysis of Variegate Porphyria (VP) in Italy: Identification of six novel mutations in the protoporphyrinogen oxidase (PPOX) gene

Cited by 4 publications

References 26 publications

Genetic and biochemical studies in Argentinean patients with variegate porphyria

Genetic and biochemical studies in Argentinean patients with variegate porphyria

Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology

Porphyrien

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