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Inheritance in protoporphyria. Comparison of haem synthetase activity in skin fibroblasts with clinical features
Insights
Deficient haem synthetase activity, crucial for haem production, is identified in children with protoporphyria and their parents. This finding supports a genetic basis for the disorder.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Protoporphyria is a metabolic disorder characterized by the accumulation of porphyrins.
- The enzyme haem synthetase plays a critical role in the heme biosynthesis pathway.
Purpose of the Study:
- To investigate the activity of haem synthetase in individuals with protoporphyria.
- To determine the inheritance pattern of haem synthetase deficiency in families with protoporphyria.
Main Methods:
- Enzyme activity assays of haem synthetase were performed on cultured skin fibroblasts.
- Activity of delta-aminolaevulinic acid synthetase was also measured.
- Clinical data including photosensitivity and erythrocyte protoporphyrin levels were analyzed.
Main Results:
- Cultured fibroblasts from protoporphyria patients and affected parents showed significantly reduced haem synthetase activity compared to controls.
- The deficient haem synthetase activity levels were similar in affected children and their carrier parents.
- Normal delta-aminolaevulinic acid synthetase activity excluded a generalized defect in heme pathway enzymes.
Conclusions:
- Reduced haem synthetase activity is the primary defect in protoporphyria.
- The disorder is likely inherited in an autosomal dominant pattern.
Abstract:
The activity of haem synthetase, the enzyme which chelates iron to protoporphyrin to form haem, was measured in cultured skin fibroblasts of children with protoporphyria and their parents from three families. In each family, one parent had deficient haem synthetase activity (3-0-11-1 pmol protohaem formed/mg protein/h) when compared to values in eight non-porphyric controls (means 24-9, range 13-7-51-5). The level of activity in the three parents was similar to that in their affected children. In two families the parent with deficient activity was also thought to be the carrier of the abnormal gene, as judged from a history of photosensitivity and analysis of erythrocyte protoporphyrin concentrations, but in the third family the pattern of inheritance could not be determined from these criteria. The activity of delta-aminolaevulinic acid synthetase was normal in cultured fibroblasts from the protoporphyric children and their parents, excluding a generalised defect in haem-pathway enzymes. These results support the premise that deficient haem synthetase activity, inherited in an autosomal dominant patter, is the primary defect in protoporphyria.