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Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria
J C Deybach1, H Puy, A M Robréau
1Centre Français des Porphyries, INSERM U409, Hôpital Louis Mourier, Colombes, France.
Abstract:
Variegate porphyria (VP) is an acute hepatic porphyria with autosomal dominant inheritance due to a partial deficiency of protoporphyrinogen oxidase (PPOX) activity. The molecular defect responsible for VP was investigated by sequencing PPOX gene coding sequence from four patients in three unrelated VP families of French Caucasian origin. In a first patient, a point insertion of a G at position 1022 of the cDNA, produced a frameshift resulting in a premature stop codon. In three other patients from two unrelated families we found a missense point mutation leading to glycine to arginine substitution (G232R) in exon 7. This Gly232 appears to be a strictly conserved residue through evolution. In one VP family, we observed the cosegregation of the G232R missense mutation and the deficient PPOX activity. The mutations reported here are the first to be described in patients with VP and support the conclusion that PPOX gene defects are disease causing mutations in human variegate porphyria.
Insights
Variegate porphyria (VP) is caused by mutations in the PPOX gene. Researchers identified novel PPOX gene mutations in French VP patients, confirming their role in this rare genetic disorder.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Variegate porphyria (VP) is an autosomal dominant acute hepatic porphyria.
- It results from a partial deficiency in protoporphyrinogen oxidase (PPOX) activity.
Purpose of the Study:
- To investigate the molecular defects causing VP in French Caucasian patients.
- To identify specific mutations within the PPOX gene responsible for the disease.
Main Methods:
- Sequencing of the PPOX gene coding sequence.
- Analysis of four patients from three unrelated VP families.
- Genetic analysis to identify mutations and assess their cosegregation with the disease.
Main Results:
- A frameshift mutation due to a G insertion at cDNA position 1022 was identified in one patient.
- A missense mutation (G232R) in exon 7 of the PPOX gene was found in three patients from two families.
- The G232R mutation cosegregated with deficient PPOX activity in one family.
Conclusions:
- These findings represent the first described mutations in patients with VP.
- Defects in the PPOX gene are confirmed as the cause of human variegate porphyria.