ALAD porphyria

ALAD porphyria is a rare porphyric disorder, with five documented compound heterozygous patients, and it is caused by a profound lack of porphobilinogen synthase (PBGS) activity. PBGS, also called "delta-aminolevulinate dehydratase," is encoded by the ALAD gene and catalyzes the second step in the biosynthesis of heme. ALAD porphyria is a recessive disorder.¸

Human PBGS exists as an equilibrium of functionally distinct quaternary structure assemblies, known as "morpheeins," in which one functional homo-oligomer can dissociate, change conformation, and reassociate into a different oligomer. In the case of human PBGS, the two assemblies are a high-activity octamer and a low-activity hexamer. The current study quantifies the morpheein forms of human PBGS for the common and porphyria-associated variants.

All porphyria-associated human PBGS variants are found to shift the morpheein equilibrium for PBGS toward the less active hexamer.

The disequilibrium of morpheein assemblies broadens the definition of conformational diseases beyond the prion disorders. ALAD porphyria is the first example of a morpheein-based conformational disease.

References

 Jaffe EK, Stith L. ALAD porphyria is a conformational disease. Am J Hum Genet. 2007 Feb;80(2):329-37. PMID: 17236137