The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development

Abstract

Nephronophthisis (NPH) is an autosomal recessive renal disease leading to kidney failure in children and young adults. The protein products of the corresponding genes (NPHPs) are localized in primary cilia or their appendages. Only about 70% of affected individuals have a mutation in one of 100 renal ciliopathy genes, and no unifying pathogenic mechanism has been identified. Recently, some NPHPs, including NIMA-related kinase 8 (NEK8) and centrosomal protein 164 (CEP164), have been found to act in the DNA-damage response pathway and to contribute to genome stability. Here, we show that NME/NM23 nucleoside-diphosphate kinase 3 (NME3) that has recently been found to facilitate DNA-repair mechanisms binds to several NPHPs, including NEK8, CEP164, and ankyrin repeat and sterile α motif domain–containing 6 (ANKS6). Depletion of nme3 in zebrafish and Xenopus resulted in typical ciliopathy-associated phenotypes, such as renal malformations and left-right asymmetry defects. We further found that endogenous NME3 localizes to the basal body and that it associates also with centrosomal proteins, such as NEK6, which regulates cell cycle arrest after DNA damage. The ciliopathy-typical manifestations of NME3 depletion in two vertebrate in vivo models, the biochemical association of NME3 with validated NPHPs, and its localization to the basal body reveal a role for NME3 in ciliary function. We conclude that mutations in the NME3 gene may aggravate the ciliopathy phenotypes observed in humans.

Ciliopathies and the Kidney: A Review

“…Additionally, digenic and triallelic inheritance have been shown to occur in NPHP, affecting the ciliopathy protein complexes and their resultant biochemical and genetic interactions that further modify observed NPHP phenotypes 76,84 . Explorative studies have been utilized to determine additional pathogenic mechanisms underlying NPHP; specific metabolic networks and DNA damage repair pathways have since been implicated 82,85,86 . Although renal ciliopathies are typically classified according to characteristic kidney pathologies, they often exhibit extra-renal manifestations as a result of the ubiquitous and multi-organ presence of primary cilia throughout the body.…”

DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

“…6 Thus, ciliary dysfunction may differentially affect a variety of tissues including the brain, retina, heart, respiratory tract, skeleton, kidneys and urogenital tract. [7][8][9][10][11][12][13][14] As a consequence, dysfunction of different ciliarelated genes can cause remarkably different phenotypes across different tissues. Although several monogenic causes of ciliopathies have been identified, 15 different alleles of the same gene can also cause strikingly diverse disease phenotypes.…”

Extensive Inter-Cyst DNA Methylation Variation in Autosomal Dominant Polycystic Kidney Disease Revealed by Genome Scale Sequencing

“…In ciliopathies, the relationship between cellular stress and the role of DDR pathways is becoming increasingly apparent (Johnson and Collis, 2016;Zhang et al, 2019). Largely identified in nephronophthisis, mutations within DDR genes such as ZNF423, CEP164, NME3, and AATF are sufficient to cause disease via ciliary dysfunction Hoff et al, 2018;Jain et al, 2019). Additionally, FAN1 inactivation triggers chronic kidney disease in zebrafish via a similar mechanism (Zhou et al, 2012).…”