ClinVar

In an 18-year-old French girl with erythropoietic porphyria-2 (EPP2; 618015), Yien et al. (2017) identified a heterozygous c.1102G-A transition (c.1102G-A, NM_006660) at the exon 7 splice junction border of the CLPX gene, resulting in a gly298-to-asp (G298D) substitution at a highly conserved residue in the Walker A motif that forms part of the ATP-binding pocket. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. The patient's father and paternal uncle, who had milder forms of the disorder, also carried the mutation. In vitro functional expression studies showed that the G298D mutant CLPX protein lacked detectable ATPase activity compared to wildtype, and partially suppressed the ATPase of wildtype CLPX promoters, 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 (ALAS1, 125290 and ALAS2, 301300) and pathologic accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Erythroid cells from the patient showed modestly increased levels of ALAS2, and CRISPR-mediated disruption of CLPX caused increased ALAS1 protein levels.