Bi-allelic variants in the aminopeptidase XPNPEP3 cause mitochondrial disease with pediatric cardiomyopathy

Bi-allelic variants in XPNPEP3 are known to cause nephronophthisis-like nephropathy-1. However, recent findings indicate XPNPEP3 deficiency causes a broader phenotypic spectrum encompassing extra-renal manifestations. XPNPEP3 is suggested to be the human ortholog of ICP55, a mitochondrial protein involved in the processing and maturation of mitochondrial proteins in plants and yeast. Here, we present a family with two children affected by a homozygous splice variant in XPNPEP3. Both children exhibited early-onset renal insufficiency and progressive mixed hypertrophic and dilated cardiomyopathy, requiring cardiac transplantation during childhood. RNA and protein analysis of patient fibroblasts and cardiac tissue revealed loss of XPNPEP3 expression due to the splice variant. Assessment of explanted cardiac tissue confirmed mitochondrial dysfunction, indicated by decreased cytochrome c oxidase activity and changes in mitochondrial morphology. Although the deficiency of Xpnpep3 in zebrafish did not result in noticeable phenotypic abnormalities during early larval stages, transcriptomic and proteomic analyses revealed mitochondrial alterations. Notably, proteomic profiling identified decreased abundance of mitochondrial proteins in xpnpep3{Delta}7/{Delta}7 mutants as compared to wild-types, including those identified in our study as putative substrates of Xpnpep3. We hypothesize that impaired processing of these proteins plays a critical role in the early developmental molecular changes observed, potentially predisposing to disease and also underlies the clinical manifestations in affected children. In summary, our study underscores that loss of XPNPEP3 causes a mitochondrial disorder with varied phenotypes, including cardiomyopathy, through a molecular mechanism likely involving abnormal processing and stabilization of mitochondrial precursor proteins. Adding XPNPEP3 to cardiac and mitochondrial disease gene panels is essential for the accurate diagnosis and management of potential cardiac complications.