FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Abstract

SUMMARYChronic kidney disease (CKD) represents a major health burden1. Its central feature of renal fibrosis is not well understood. By whole exome resequencing in a model disorder for renal fibrosis, nephronophthisis (NPHP), we identified mutations of Fanconi anemia-associated nuclease 1 (FAN1) as causing karyomegalic interstitial nephritis (KIN). Renal histology of KIN is indistinguishable from NPHP except for the presence of karyomegaly2. FAN1 has nuclease activity, acting in DNA interstrand crosslinking (ICL) repair within the Fanconi anemia pathway of DNA damage response (DDR)3–6. We demonstrate that cells from individuals with FAN1 mutations exhibit sensitivity to the ICL agent mitomycin C. However, they do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from patients with Fanconi anemia. We complement ICL sensitivity with wild type FAN1 but not mutant cDNA from individuals with KIN. Depletion of fan1 in zebrafish revealed increased DDR, apoptosis, and kidney cysts akin to NPHP. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms of renal fibrosis and CKD.

Ccdc13; a novel human centriolar satellite protein required for ciliogenesis and genome stability

“…Interestingly, several of these are either known, or putative, substrates for the key DDR regulating kinases ATM and ATR (Matsuoka et al, 2007;Smith et al, 2009), which might point to DDR-related regulation of these proteins. Collectively, these findings, together with recent genetic studies Choi et al, 2013;Kalay et al, 2011;Sivasubramaniam et al, 2008;Stiff et al, 2013;Valdés-Sánchez et al, 2013;Zhou et al, 2012), highlight emerging functional links between centrosomal satellites, the DNA damage response, genome stability and human ciliopathies (Chavali and Gergely, 2013). These findings open up new exciting avenues of research and suggest that mutations in other DDR-related proteins might be causal for a subset of human ciliopathies, and that, potentially, mutations in some centrosomal satellite proteins might be causal for a subset of cancer predisposition disorders.…”

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

“…[65]. Instead, biallelic lack-of-function point mutations in FAN1 cause karyomegalic interstitial nephritis, linking chronic kidney failure to ICLR [66].Further,in contrast to ERCC4-ERCC1, FAN1 activity (similarly to MUS81-EME1 activity) is not required for nucleolytic incisions near an ICL [67]. Therefore, the role of FAN1 nuclease activity in the FA pathway is still under discussion.…”

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

“…By depletion of fan1 in zebrafish we recapitulated increased DDR, apoptosis, and kidney cysts akin to NPHP. 72 We suggest a working hypothesis for the pathogenesis of certain forms of NPHP-RC proposing the following cascade of events: defects of DDR lead to a lack of Chk1 (Chk2) activation, thereby causing inadequate G 2 /M cell cycle arrest. This would lead in high proliferation states (high replication stress) during morphogenesis to dysplastic phenotypes (Meckel syndrome) and in low proliferation states (low replication stress) during tissue maintenance and repair to tissue degeneration and fibrosis (nephronophthisis).…”