A mutation in the iron-responsive element of ALAS2 is a modifier of disease severity in a patient suffering from CLPX associated erythropoietic protoporphyria

Abstract

Porphyrias are a group of eight genetically distinct disorders, each resulting from a partial deficiency or gain-offunction of a specific enzyme in the heme biosynthetic pathway.1 Porphyrias are inherited as autosomal dominant, autosomal recessive or X-linked traits.2 Erythropoietic protoporphyria (EPP) is a constitutive hematological disorder characterized by protoporphyrin IX (PPIX) accumulation in erythrocytes and other tissues resulting in acute skin photosensitivity, mild microcytic anemia, and rarely, severe liver disease. The majority of the patients with EPP present the autosomal EPP form (OMIM #177000) due to a partial deficiency of ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway.1,2 In most EPP patients, the clinical expression requires the coinheritance of a FECH mutation, that abolishes or markedly reduces FECH activity, in trans to an hypomorphic FECH allele (rs2272783, NM_000140.3; c.[315-48T>C]) carried by about 11% of Caucasians.3 In Europe and the USA, 4-10% of EPP patients have been reported to harbor a gain-of-function mutation in the 11th exon of the erythroid d-aminolevulinic synthase gene (ALAS2).4 Rare cases of EPP have also been reported in few reference centers without any mutations in the FECH or ALAS2 genes (personal communication from JC Deybach). EPP due to gain-of-function ALAS2 mutations are inherited as an X-linked trait and result in a distinct biochemical feature not only with overproduction and accumulation of free PPIX but also zinc protoporphyrin (ZnPP) (XLPP) (OMIM #300751). In these patients, the FECH enzyme is functional and utilizes all available iron for heme production. The excess PPIX is used to make ZnPP in a reaction catalyzed by FECH.3,5 Moreover, gain-of-function missense mutations altering the C-terminal part of ALAS2 exacerbate congenital erythropoietic porphyria, suggesting that ALAS2 is a gatekeeper of erythroid heme biosynthesis and may function as a modifier gene.6