Figure 1.

Pedigree Structure, PPA2 Genomic Organization Conservation, and Family 1 Variant Modeling

(A) Pedigrees of four families identified with mutations in PPA2 (GenBank: NM_176869.2) encoding the mitochondrial inorganic pyrophosphatase. Individuals with a question mark have not been tested. Mutations found in more than one family are colored.

(B) Location of mutations within the gene, and phylogenetic conservation of the predicted missense mutations.

(C) Space fill model showing position of p.Pro228 at boundary of dimers and p.Glu172 in the active site produced in CN3D with reference PDB: 1M38.

(D) Left: Structural model of one molecule of PPA2 showing the position of four mutations in folded structure (red). Residues that are known to be critical to PPA2 function in S. cerevisiae are highlighted in yellow.¹⁹ Right: Space fill of the PPA2 active site showing three substitutions are located at the surface of the active site. Models produced using Swiss-PdbViewer²⁰ (with reference PDB: 1M38).