EU funded studies link degenerative diseases that affect kidney, retina and brain to defective DNA damage repair.
EU funded studies link degenerative diseases that affect kidney, retina and brain to defective DNA damage repair. For reasons not well understood, chronic kidney disease is on the rise in developed countries. The biology of renal fibrosis, it’s central feature, also remains a mystery. Associate Professor Rachel Giles, PhD, from UMC Utrecht and her group participate in the FP7 SYSCILIA project, which partly funded the study that links degenerative diseases to defective DNA damage repair. SYSCILIA, part of the ‘Health’ Theme of the EU’s Seventh Framework Programme (FP7), takes a systems biology approach to dissect cilia function and its disruption in human genetic disease. Recently, together with colleagues from seven other countries, Giles described in Nature Genetics [44(8), 910-5, August 2012] new gene mutations that cause the very rare genetic kidney disorder KIN (karyomegalic interstitial nephritis). Children suffering from KIN suffer from prematurely ageing kidneys. Their kidneys look like organs from elderly persons. Giles and colleagues found in 9 out of 10 examined families that mutations in the FAN1 gene caused this rare disease. It fits with the function of the FAN1 protein, which is involved in DNA repair. Apparently, in KIN patients, kidney cells are unable to repair DNA damage, which accelerates the ageing process, specifically in the kidney. UMC Utrecht researchers confirmed the FAN1 impact on kidneys by altering the gene in zebrafish. The health implications of the finding may seem limited. Prior to this publication only 15 families worldwide were known to suffer from KIN. But the link between cellular ageing and kidney disease is a new one, and suggests a whole new cause of kidney disease. “We believe”, Giles says, “that this mechanism explains how factors like DNA damage cause kidney disease in the general public. It would for example explain why children with relatively ‘young’ organs sometimes exhibit kidney diseases typically associated with the ageing population.” A paper in the prestigious journal Cell [150, 533-48, August 3, 2012] confirms the link between DNA damage and kidney disease. In this paper they link renal ciliopathies to DNA damage response signaling. An international team of researchers, of which 6 groups are funded from the SYSCILIA project, has identified by whole-exome resequencing disease causing mutations in 3 genes that function within the DNA damage response pathway. Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies.” However, disease mechanisms remain poorly understood. Less than 50% of all cases with NPHP-RC have mutations in known NPHP-genes. Some of the recently identified genetic causes of NPHP-RC are exceedingly rare which necessitates the ability to identify novel single-gene causes of NPHP-RC in single affected families. To achieve this goal, a strategy was developed that combines homozygosity mapping with whole-exome resequencing. Because this approach allows identification of multiple different causes of NPHP-RC within a short timeframe, it has the potential of delineating pathogenic pathways. Using this approach, the study identified mutations in three NPHP-RC genes, MRE11, ZNF423 and CEP164, which together suggest involvement of a DDR signaling pathway in NPHP-RC pathogenesis. Based on their findings the researchers propose a pathogenic hypothesis for NPHP-RC that implicates DDR signaling as a relevant disease mechanism. Within this hypothesis, loss of function of NPHP-RC proteins with a dual role in DDR and centrosomal signaling, would cause disturbance of cell-cycle checkpoint control. The link between degenerative diseases and DNA damage response signaling, causing impaired cell-cycle checkpoint control might provide a mechanism for the dual phenotypes of degeneration/dysplasia seen in NPHP-RC in kidney, eye, cerebellum and liver. The degenerative phenotypes would be characterized as diseases of “organ-specific premature aging”, thereby pointing in new directions for the identification of small compounds for therapy.
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