Homozygous Variegate Porphyria: 20 y Follow-Up and Characterization of Molecular Defect

Kauppinen, Raili; von, Mikael; Fraunberg, und zu; Ahola, Helena; Mustajoki, Pertti; Timonen, Kaisa; Laitinen, E Kalevi A; Tenhunen, Raimo; Taketani, Shigeru

doi:10.1046/j.1523-1747.2001.01293.x

Cited by 32 publications

(26 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Six of the Finnish VP mutations are family-specific and found so far only in Finland, whereas the major mutation (R152C), which was identified in 11 (52%) of the 21 Finnish VP families, has also been reported in France and in the USA. 29,31 As previously reported, 40,41 six of the mutations have been expressed in prokaryotic and eukaryotic cell systems. The PPOX activities of the mutated polypeptides were markedly reduced (45% , Table 1) confirming that the mutations are responsible for the disease.…”

Section: Introductionmentioning

confidence: 57%

“…The family became aware of VP mainly due to a homozygous patient with a severe phenotype. 40 The occurrence of photosensitivity was significantly lower in the I12T group compared to the R152C group (P=0.001), whereas no significant differences between the R152C and 338G?C groups could be observed.…”

Section: Resultsmentioning

confidence: 81%

“…Interestingly, the homozygous patient with the I12T mutation demonstrated as high as 10% residual activity in vivo, which is sufficient to enable the patient to survive. 40 Alternatively, another familial factor may be present in the subjects with the I12T mutation that influences their phenotype.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Clinical and biochemical characteristics and genotype–phenotype correlation in Finnishvariegate porphyria patients

et al. 2002

Self Cite

View full text Add to dashboard Cite

Variegate porphyria (VP) is an inherited metabolic disease resulting from the partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway. We have evaluated the clinical and biochemical outcome of 103 Finnish VP patients diagnosed between 1966 and 2001. Fifty-two per cent of patients had experienced clinical symptoms: 40% had photosensitivity, 27% acute attacks and 14% both manifestations. The proportion of patients with acute attacks has decreased dramatically from 38 to 14% in patients diagnosed before and after 1980, whereas the prevalence of skin symptoms had decreased only subtly from 45 to 34%. We have studied the correlation between PPOX genotype and clinical outcome of 90 patients with the three most common Finnish mutations I12T, R152C and 338G?C. The patients with the I12T mutation experienced no photosensitivity and acute attacks were rare (8%). Therefore, the occurrence of photosensitivity was lower in the I12T group compared to the R152C group (P=0.001), whereas no significant differences between the R152C and 338G?C groups could be observed. Biochemical abnormalities were significantly milder suggesting a milder form of the disease in patients with the I12T mutation. In all VP patients, normal excretion of protoporphyrin in faeces in adulthood predicted freedom from both skin symptoms and acute attacks. The most valuable test predicting an increased risk of symptoms was urinary coproporphyrin, but only a substantially increased excretion exceeding 1000 nmol/day was associated with an increased risk of both skin symptoms and acute attacks. All patients with an excretion of more than 1000 nmol/day experienced either skin symptoms, acute attacks, or both.

show abstract

Section: Introductionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 81%

See 1 more Smart Citation

Clinical and biochemical characteristics and genotype–phenotype correlation in Finnishvariegate porphyria patients

et al. 2002

Self Cite

View full text Add to dashboard Cite

show abstract

“…Seven mutations selected for this study were previously identified from Finnish VP patients and expressed in Escherichia coli and COS-1 cells (Table I) (21,22).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Targeting of Normal and Mutant Protoporphyrinogen Oxidase

Fraunberg

Nyrönen

Kauppinen

2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

We have investigated the signal sequence for mitochondrial transport of mutants (I12T, 78insC, IVS2-2a3c, 338G3 C, R152C, 470A3 C, and L401F) and the wild type protoporphyrinogen oxidase (PPOX), which is the penultimate enzyme in the heme biosynthesis. We constructed the corresponding green fluorescent protein fusion proteins and studied their intracellular localization in COS-1 cells. We showed that 28 amino acids in the amino terminus of PPOX contain an independently functioning signal for mitochondrial targeting. The experiments with amino-terminally truncated green fluorescent protein fusion proteins revealed that amino acids 25-477 of PPOX contained an additional mitochondrial targeting signal(s). We constructed a structural model for the interaction between the aminoterminal end of PPOX and the putative mitochondrial receptor protein Tom20. The model suggests that leucine and isoleucine residues Leu-8, Ile-12, and Leu-15 forming an ␣-helical hydrophobic motif, LXXXIXXL, were crucial for the recognition of the targeting signal. The validity of the model was tested using mutants L8Q, I12T, and L15Q disrupting the hydrophobic surface of the LXXXIXXL helix. The results from in vitro expression studies and molecular modeling were in accordance supporting the hypothesis that the recognition of the mitochondrial targeting signal is dependent on hydrophobic interactions between the targeting signal and the mitochondrial receptor.

show abstract

“…Most patients are heterozygous, exhibiting approximately 50% reduced PPOX activity (Brenner and Bloomer 1980;Deybach et al 1981). However, since the first description of a homozygous VP case in 1984 (Korda et al 1984), several homozygous and compound heterozygous cases have been reported (Hift et al 1993;Kauppinen et al 2001;Poblete-Gutiérrez et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of Five Protoporphyrinogen oxidase Missense Mutations Found in Argentinean Variegate Porphyria Patients

et al. 2011

View full text Add to dashboard Cite

A partial deficiency in protoporphyrinogen oxidase (PPOX) produces the acute/cutaneous (or mixed) variegate porphyria (VP), the third most frequent porphyria in Argentina. This autosomal dominant disorder is clinically characterized by skin lesions and/or acute neurovisceral attacks. The precise diagnosis of patients with a symptomatic VP is essential to provide accurate treatment. It is also critical to identify asymptomatic relatives to avoid precipitating factors and prevent acute attacks.Functional consequences of five PPOX missense mutations were evaluated in a prokaryotic expression system.

show abstract

Homozygous Variegate Porphyria: 20 y Follow-Up and Characterization of Molecular Defect

Cited by 32 publications

References 18 publications

Clinical and biochemical characteristics and genotype–phenotype correlation in Finnishvariegate porphyria patients

Clinical and biochemical characteristics and genotype–phenotype correlation in Finnishvariegate porphyria patients

Mitochondrial Targeting of Normal and Mutant Protoporphyrinogen Oxidase

Functional Characterization of Five Protoporphyrinogen oxidase Missense Mutations Found in Argentinean Variegate Porphyria Patients

Contact Info

Product

Resources

About