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ALAD porphyria is a conformational disease
1Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Eileen.Jaffe@fccc.edu
American Journal of Human Genetics
|January 20, 2007
Summary
ALAD porphyria results from reduced porphobilinogen synthase (PBGS) activity due to altered ALAD gene variants. These variants shift PBGS protein structure towards a less active hexamer form, causing this rare metabolic disorder.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- ALAD porphyria is a rare genetic disorder caused by deficient porphobilinogen synthase (PBGS) activity.
- PBGS, encoded by the ALAD gene, is crucial for heme biosynthesis.
- Human PBGS exhibits quaternary structure polymorphism, existing as distinct functional assemblies called morpheeins (octamer and hexamer).
Purpose of the Study:
- To quantify the morpheein assembly distribution for common and porphyria-associated ALAD variants.
- To investigate the impact of ALAD mutations on PBGS quaternary structure and activity.
- To establish ALAD porphyria as a novel class of morpheein-based conformational disease.
Main Methods:
- Heterologous expression of ALAD variants in Escherichia coli.
- Separation of PBGS octameric and hexameric assemblies using ion-exchange chromatography.
- Kinetic analysis to assess the functional impact of morpheein assembly shifts.
Main Results:
- Porphyria-associated ALAD variants significantly increased the percentage of the low-activity PBGS hexamer compared to wild-type.
- Specific variants like F12L and R240W showed 100% and 80% hexamer formation, respectively.
- All eight studied porphyria-associated variants demonstrated a propensity to form the hexamer, shifting the morpheein equilibrium.
Conclusions:
- ALAD porphyria is characterized by a shift in PBGS morpheein equilibrium towards the less active hexamer.
- This study proposes morpheein disequilibrium as a mechanism for conformational diseases beyond prion disorders.
- ALAD porphyria represents the first identified morpheein-based conformational disease.
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