FAN1 – Karyomegalic Interstitial Nephritis

Karyomegalic interstitial nephritis (KIN) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the FAN1 gene. Clinically, KIN presents in early to mid adulthood with progressive chronic kidney disease, nonselective proteinuria, microscopic hematuria, and enlarged tubular epithelial nuclei on biopsy. Extrarenal features such as mild transaminase elevation, recurrent respiratory infections, bronchiectasis, and cancer risk post-transplantation have been reported (PMID:27196444; PMID:31655823).

Genetic evidence supporting a strong FAN1–KIN association includes identification of LoF variants in eight probands across seven unrelated families, with confirmed segregation in six additional affected relatives (PMID:27196444; PMID:31655823; PMID:32111193; PMID:33273795; PMID:35896079; PMID:38847221; PMID:39294548). All cases follow autosomal recessive inheritance, often in consanguineous pedigrees.

The FAN1 variant spectrum in KIN is dominated by protein-truncating mutations (nonsense, frameshift, splice site), with recurrent c.2616del (p.Asp873ThrfsTer17) observed in multiple families (PMID:27196444; PMID:34126972). Missense changes are rare, and no founder effect has been documented beyond isolated populations.

Functional studies demonstrate that loss of FAN1 nuclease activity leads to defective DNA interstrand cross-link repair and hypersensitivity to endogenous ROS. Fan1⁻/⁻ mice develop a KIN-like phenotype upon chronic cisplatin exposure, and FAN1-deficient human tubular cells accumulate DNA damage and oxidative stress, rescuable by ROS scavengers (PMID:27026368; PMID:37107275). These concordant animal and cellular data support haploinsufficiency of FAN1 in renal tubular repair.

A case of KIN without FAN1 mutations following brentuximab and carboplatin exposure indicates that drug-induced mechanisms can phenocopy genetic KIN, underscoring the need for molecular confirmation in atypical presentations (PMID:39543462).

In summary, biallelic FAN1 truncating variants cause KIN through defective DNA repair in renal tubular epithelium. Genetic testing of FAN1 is recommended for adults with unexplained CKD, karyomegaly on biopsy, and associated extrarenal features. Identification of FAN1 mutations informs prognosis, transplant risk stratification, and family planning.

References

• Medicine • 2016 • Karyomegalic Interstitial Nephritis: A Case Report and Review of the Literature. PMID:27196444
• Nephron • 2020 • Karyomegalic Interstitial Nephritis: Cancer Risk Following Transplantation. PMID:31655823
• BMC Nephrology • 2020 • Karyomegalic interstitial nephritis with a novel FAN1 gene mutation and concurrent ALECT2 amyloidosis. PMID:32111193
• Indian Journal of Nephrology • 2020 • Novel Homozygous FAN1 Mutation in a Familial Case of Karyomegalic Interstitial Nephritis. PMID:33273795
• Nephron • 2023 • Heterozygous Variants in a Patient with Karyomegalic Interstitial Nephritis. PMID:35896079
• Journal of the American Society of Nephrology • 2016 • A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis. PMID:27026368
• Antioxidants • 2023 • Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys. PMID:37107275
• BMC Nephrology • 2024 • A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure. PMID:39543462

Evidence Based Scoring (AI generated)