SNOMEDCT: 782738008; ORPHA: 401996; DO: 0060911;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q13.3 | Interstitial nephritis, karyomegalic | 614817 | Autosomal recessive | 3 | FAN1 | 613534 |
A number sign (#) is used with this entry because karyomegalic interstitial nephritis (KMIN) is caused by homozygous or compound heterozygous mutation in the FAN1 gene (613534) on chromosome 15q13.
Karyomegalic tubulointerstitial nephritis (KMIN) is a rare kidney disease characterized clinically by onset in the third decade of progressive renal failure. Renal biopsy shows chronic tubulointerstitial nephritis and interstitial fibrosis associated with enlarged and atypical tubular epithelial cell nuclei (summary by Baba et al., 2006).
Spoendlin et al. (1995) reported 3 unrelated adult patients who presented with asymptomatic, slowly progressive renal dysfunction identified by routine laboratory investigation. Two patients had proteinuria, and 1 had hypertension. All had a history of recurrent infections earlier in life. Urine cytology of a son of one of the patients showed a few cells with enlarged nuclei; his renal function was normal. Renal biopsy in the 3 probands showed markedly enlarged and hyperchromatic nuclei in tubular epithelial cells in all parts of the nephron. Electron microscopy showed bizarrely enlarged nuclei with an irregular distribution of chromatin. In all cases, there was interstitial fibrosis surrounding atrophic tubules, and some of the glomeruli were completely sclerosed. Immunohistochemical studies showed significantly increased PCNA (176740), suggesting active DNA synthesis and perhaps an inhibition of mitosis in these cells. Spoendlin et al. (1995) postulated a genetic defect causing an induction of DNA repair.
Godin et al. (1996) reported a French brother and sister with onset of progressive renal failure at ages 32 and 42 years, respectively. Neither had a history of recurrent infections. Both had mild proteinuria and glycosuria. Both had persistent elevation of liver enzymes, which was more marked in the brother, but his liver biopsy was normal. Renal biopsies of both patients showed enlarged and hyperchromatic nuclei in tubular epithelial cells as well as in endothelial cells of the peritubular capillaries. Both had high levels of blood and urine ochratoxin A, a mycotoxin known to be nephrotoxic. The brother underwent renal transplantation and had normal renal function 10 years later.
Baba et al. (2006) reported a 39-year-old man who presented with asymptomatic progressive renal failure. He also had mild hypertension and mildly increased liver enzymes. Renal biopsy showed globally sclerosed glomeruli, interstitial fibrosis with tubular atrophy, and karyomegaly in tubular epithelial cells. Electron microscopy showed uneven chromatin distribution in the nuclei. The disorder progressed to stage IV chronic renal failure and the patient was worked-up for transplantation.
Monga et al. (2006) reported 2 Italian sibs, born of consanguineous parents, with karyomegalic interstitial nephritis. The patients presented at ages 31 and 22 years, respectively. The older sister had a history of repeated respiratory infections. At age 38, she had severe renal failure. Renal biopsy showed hyalinized glomeruli, large nuclei in tubular epithelial cells, atrophic tubules, and interstitial fibrosis. Karyomegalic changes were also noted in a skin biopsy and liver biopsy. She underwent kidney transplantation at age 42, but died 20 days later. Postmortem examination showed karyomegalic cells in multiple tissues, including endothelial cells in the brain and lung, fibroblasts of the thyroid and myocardium, Schwann cells, the esophagus, and smooth muscle cells of the aorta. Her younger brother had severe chronic renal failure and chronic liver disease with increased liver enzymes and cholestasis. Renal biopsy was similar to his sister's, with hyperchromatic nuclei and nuclei with dispersed chromatin. Karyomegalic cells were also observed in a duodenal biopsy. He developed chronic renal failure requiring dialysis and died 6 years after presentation. Monga et al. (2006) also reported an unrelated Italian man with a less severe form of the disorder.
Palmer et al. (2007) reported a 44-year-old Maori woman who presented with pneumonia and was found to have renal insufficiency on biochemical studies. She also had normocytic anemia requiring transfusion. Renal ultrasound showed atrophic and echogenic kidneys, and urinalysis showed protein and glucose. Renal biopsy revealed karyomegalic changes in the tubules, dilated tubules, and tubular atrophy. Cytology of the urine showed irregular, large, vesicular nuclei with prominent nucleoli and atypical features, which Palmer et al. (2007) noted could mimic carcinoma. Family history revealed a brother with karyomegalic interstitial nephritis.
Verine et al. (2010) reported a 50-year-old French woman who presented with asymptomatic renal failure and mild proteinuria without hematuria. Renal biopsy showed large tubulointerstitial fibrosis and massively enlarged tubular epithelial cell nuclei, consistent with karyomegalic interstitial nephritis. Family history revealed a brother who died of renal insufficiency at 35 years of age. In the patient reported by Verine et al. (2010), Zhou et al. (2012) identified compound heterozygous mutations in the FAN1 gene (613534.0005 and 613534.0006).
The transmission pattern of karyomegalic interstitial nephritis in the families reported by Zhou et al. (2012) was consistent with autosomal recessive inheritance.
In affected members of 9 unrelated families with karyomegalic interstitial nephritis, Zhou et al. (2012) identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene (see, e.g., 613534.0001-613534.0008). Eight of the 12 mutations resulted in a truncated protein. The first mutation was identified by homozygosity mapping and exome sequencing in an affected family reported by Palmer et al. (2007). Other families with mutations had been reported by Godin et al. (1996), Spoendlin et al. (1995), and Baba et al. (2006). Upon exposure to mitomycin C, FAN1 mutant cells showed genomic instability, as manifest by increased chromatid breaks and radial chromosomes on metaphase spreads. Although the results of the test for Fanconi anemia (see, e.g., 227650), diepoxybutane-induced breakage, were negative in FAN1-mutant cells lines, these cells still showed decreased survival compared to wildtype in response to either inducer of interstrand crosslink repair (ICL). None of the FAN1 mutant proteins was able to correct mitomycin C-induced decreased survival in cells lacking FAN1 nuclease activity. Morpholino knockdown of Fan1 in zebrafish embryos resulted in a nephronophthisis (NPHP; 256100)-like phenotype, with shortened and curved body axis, as well as a Fanconi anemia-like phenotype, with microcephaly, microphthalmia, and massive apoptosis. There was evidence of activation of the DNA damage repair pathway, as demonstrated by increased signaling for gamma-H2AX (H2AFX; 601772). Knockdown of both Fan1 and p53 (191170) in zebrafish caused renal cysts, reminiscent of a ciliopathy. In the fawn-hooded hypertensive rat, an animal model of chronic kidney disease, as well as in kidney samples from humans with genetically heterogeneous forms of chronic kidney disease, Zhou et al. (2012) found increased nuclear staining for gamma-H2AX, indicating activation of the DNA damage response pathway. These findings supported the hypothesis that DNA lesions and DNA damage response pathways may partially drive renal damage in NPHP-related ciliopathies and in chronic kidney disease.
Baba, F., Nanovic, L., Jaffery, J. B., Friedl, A. Karyomegalic tubulointerstitial nephritis--a case report. Path. Res. Pract. 202: 555-559, 2006. [PubMed: 16678356] [Full Text: https://doi.org/10.1016/j.prp.2006.02.004]
Godin, M., Francois, A., Le Roy, F., Morin, J.-P., Creppy, E., Hemet, J., Fillastre, J.-P. Karyomegalic interstitial nephritis. (Letter) Am. J. Kidney Dis. 27: 166 only, 1996. [PubMed: 8546134] [Full Text: https://doi.org/10.1016/s0272-6386(96)90047-5]
Monga, G., Banfi, G., Salvadore, M., Amatruda, O., Bozzola, C., Mazzucco, G. Karyomegalic interstitial nephritis: report of 3 new cases and review of the literature. Clin. Nephrol. 65: 349-355, 2006. [PubMed: 16724656] [Full Text: https://doi.org/10.5414/cnp65349]
Palmer, D., Lallu, S., Matheson, P., Bethwaite, P., Tompson, K. Karyomegalic interstitial nephritis: a pitfall in urine cytology. Diagn. Cytopathol. 35: 179-182, 2007. [PubMed: 17304531] [Full Text: https://doi.org/10.1002/dc.20603]
Spoendlin, M., Moch, H., Brunner, F., Brunner, W., Burger, H.-R., Kiss, D., Wegmann, W., Dalquen, P., Oberholzer, M., Thiel, G., Mihatsch, M. J. Karyomegalic interstitial nephritis: further support for a distinct entity and evidence for a genetic defect. Am. J. Kidney Dis. 25: 242-252, 1995. [PubMed: 7847351] [Full Text: https://doi.org/10.1016/0272-6386(95)90005-5]
Verine, J., Reade, R., Janin, A., Droz, D. Nephrite interstitielle caryomegalique: un nouveau cas francais. Ann. Path. 30: 240-242, 2010. [PubMed: 20621605] [Full Text: https://doi.org/10.1016/j.annpat.2010.03.001]
Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nature Genet. 44: 910-915, 2012. [PubMed: 22772369] [Full Text: https://doi.org/10.1038/ng.2347]