Nature Genetics刊登: 單一基因突變(FAN1) 造成慢性腎臟病 (CKD) !!!

Researchers identify new genetic cause for chronic kidney disease  July 10, 2012 in Genetics A new single-gene cause of chronic kidney disease has been discovered that implicates a disease mechanism not previously believed to be related to the disease, according to new research from the University of Michigan.  The research was published July 8 in the journal Nature Genetics. "In developed countries, the frequency of chronic kidney disease is continually increasing for unknown reasons. The disease is a major health burden," says Friedhelm Hildebrandt, M.D., the paper's senior author and professor of pediatrics and of human genetics at C.S. Mott Children's Hospital. Using whole exome sequencing, Hildebrandt and his colleagues studied a model disorder for renal fibrosis, nephronophthisis, and detected a new single-gene cause of CKD that implicates a disease mechanism formerly not related to CKD — DNA damage response signaling (DDR). "Since DNA damage is cause by a whole variety of chemical compounds it may now be important to see whether certain 'genotoxins' may play a role in the increase of CKD," says Hildebrandt who is also an investigator for the Howard Hughes Medical Institute. The researchers identified mutations of Fanconi anemia-associated nuclease 1 (FAN1) as causing karyomegalic interstitial nephritis (KIN) in patients with CKD. Depletion of fan1 in a zebrafish model of disease revealed increased DDR, apoptosis, and kidney cysts akin to nephronophthisis. "Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms of renal fibrosis and CKD," Hildebrandt said. Journal reference: Nature Genetics Provided by University of Michigan Health System  

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

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.