Genotype-Phenotype Correlations in Porphyria

Abstract

The porphyrias are a group of disorder resulting from defects in the haem biosynthesis pathway. The majority of defects are genetic in origin. The clinical penetrance of porphyria is variable and cannot be explained by environmental factors alone. It is therefore likely that genetic modifiers are present to influence the phenotypic outcome of the disease. In the first part of this study, variants in ABCB6, a member of the ATP-Binding Cassette transporter, were detected in a high proportion (62.5%) of severely affected porphyria patients. In vitro functional studies revealed that these ABCB6 variants either affect dimer formation (p.Arg276Trp, p.Thr521Ser, p.Gly588Ser and p.Ala681Thr), or has decreased ATPase activity (p.Ala492Thr). In a double knock out mouse model deficiency in Fech (Fechm1Pas) and Abcb6 showed a more severe phenotype compared to Fechm1Pas-only mice. The results support that ABCB6 acts as a genetic modifier for porphyria patients. In the second part of this study, detailed study on a patient with fatal liver failure secondary to erythropoietic protoporphyria (EPP) revealed an atypical low expression FECH allele and a maternally inherited FECH p.Phe260Leu mutation giving rise to the EPP. Exome sequencing of this EPP patient and her parents revealed multiple functional variants and a novel 0.79Mb duplication, all involving genes in the bile secretion pathway. These variants affect both the basolateral re-uptake and canalicular secretion of bile acids as well as their constitution. In EPP, the excessive haem intermediate protoporphyrin IX is excreted in bile. The results here suggest that genetic variants in the bile secretion pathway may contribute to the risk of liver failure in EPP patients.