RESUMO
Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.
Assuntos
Reparo do DNA/genética , Exodesoxirribonucleases/genética , Mutação , Nefrite Intersticial/genética , Insuficiência Renal Crônica/genética , Animais , Linhagem Celular , Dano ao DNA , Endodesoxirribonucleases , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Técnicas de Silenciamento de Genes , Genes Recessivos , Teste de Complementação Genética , Humanos , Enzimas Multifuncionais , Nefrite Intersticial/complicações , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Peixe-Zebra/anormalidades , Peixe-Zebra/genéticaRESUMO
Karyomegalic interstitial nephritis (KIN) is a rare and slowly progressive chronic interstitial nephritis (CIN) (28 cases reported), described for the first time by Mihatsch et al. in 1979. Here, we report on a 50-year-old woman who presented with asymptomatic renal failure and mild proteinuria without hematuria. Renal biopsy showed large tubulo-interstitial fibrosis and massively enlarged tubular epithelial cell nuclei, without viral inclusion. KIN is a rare CIN defined by a karyomegaly of tubular epithelial cell nuclei. Its pathogenesis remains obscure. Nevertheless, an exogenous factor is suspected, ochratoxin A particularly. The familial clustering of patients and the frequency of HLA-A9 and HLA-B35 haplotypes suggest the presence of a possible genetic susceptibility to this disorder.
