Protoporphyria, Erythropoietic, 2

A number sign (#) is used with this entry because of evidence that erythropoietic protoporphyria-2 (EPP2) is caused by heterozygous mutation in the CLPX gene (615611) on chromosome 15q22. One such family has been reported.

Description

Erythropoietic porphyria-2 is an autosomal dominant metabolic disorder of heme biosynthesis, resulting in abnormal accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Affected individuals may have photosensitivity (summary by Yien et al., 2017)

For discussion of genetic heterogeneity of EPP, see EPP1 (177000).

Clinical Features

Yien et al. (2017) reported an 18-year-old French girl with congenital porphyria. She had onset of acute photosensitivity at age 9 months. Features included painful phototoxic reactions and elevated levels of free and zinc-chelated erythroid PPIX, a heme biosynthesis intermediate. At the time of diagnosis, she also had microcytic iron deficiency anemia, which may or may not have been related to the EPP. Her father and paternal uncle had mild photosensitivity and accumulation of PPIX, but without the complete clinical syndrome of EPP.

Inheritance

The transmission pattern of EPP2 in the family reported by Yien et al. (2017) was consistent with autosomal dominant inheritance with variable expressivity.

Molecular Genetics

In an 18-year-old French girl with EPP2, Yien et al. (2017) identified a heterozygous missense mutation in the CLPX gene (G298D; 615611.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells and cells transfected with the mutation showed increased ALAS (ALAS1, 125290 and ALAS2, 301300) protein and activity levels, as well as accumulation of PPIX. Injection of the mutation into zebrafish also resulted in increased ALAS activity. In vitro functional studies showed that the G298D mutant protein lacked detectable ATPase activity and caused decreased interaction with CLPP (601119). Mutant CLPX also partially suppressed the ATPase of wildtype CLPX, consistent with a dominant-negative effect. Cells with the mutant protein showed impaired CLPX-dependent turnover of ALAS, resulting in increased posttranslational stability of ALAS and pathologic accumulation of PPIX. Overall, the findings suggested that the CLPX mutation caused aberrant control of ALAS.