Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

Abstract

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

Aminopeptidase P3 (APP3), a novel member of the TNF/TNFR2 signaling complex, induces phosphorylation of JNK

“…The highest levels were in heart followed by pancreas, kidney, testis and peripheral blood mononuclear cells (PBMCs) and other tissues. Notably, a genome-wide homozygosity mapping study of families presenting with the autosomal recessive kidney disease nephronophthisis (NPHP) detected homozygous frameshift and splice-site mutations in the gene encoding APP3 (Böttinger, 2010;O'Toole et al, 2010). This earlier study revealed that APP3, which is related to ciliary dysfunction, is a potential disease-causing protein in kidney.…”

Renal manifestations of genetic mitochondrial disease

“…Mutations in XPNPEP3, a mitochondrial aminopeptidase, were identified in two independent kindred 65 with a renal phenotype characterized by tubular atrophy with interstitial fibrosis and progressive renal insufficiency. One of these kindred with an early truncating mutation presented with evidence of multiorgan system involvement and complex I deficiency in muscle biopsy.…”

“…Mutations in several other nuclear-encoded genes have been reported in individuals with spectrum respiratory chain defects, including decreased activity of complex I, 65 complex III, 68 complex IV, 69 and complex V. 70 Mutations in the mitochondrial chaperone BCS1L have been associated with complex III-deficiency encephalopathy, liver failure, and proximal tubulopathy, or rarely interstitial nephritis presenting in the neonatal period.…”

Hooked! Modeling human disease in zebrafish

“…The zebrafish system is well poised for functionally characterizing such genes and can be used to examine coding and noncoding function in vivo. Several studies using genomic approaches have identified gene variants whose function in disease pathology has been successfully tested in zebrafish, including melanoma (87), cardiomyopathy (88), polyneuropathy (89), neurodegenerative disease (90,91), and ciliopathies (92). Recently, Gieger et al carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in nearly 67,000 individuals to identify putative novel regulators of megakaryopoiesis and platelet formation (93).…”