A CASE OF SPORADIC KARYOMEGALIC INTERSTITIAL NEPHRITIS WITH A NOVEL FAN1 GENE MUTATION: THE FIRST REPORT IN EAST ASIA.

Karyomegalic interstitial nephritis (KIN) is a rare autosomal recessive disorder caused by pathogenic variants in FAN1, leading to chronic tubulointerstitial injury and progressive renal dysfunction. Its hallmark is karyomegaly—marked enlargement and atypia of tubular epithelial nuclei—resulting from defective DNA repair during regeneration. We report a Japanese patient with sporadic KIN diagnosed by biopsy, carrying compound heterozygous FAN1 frameshift mutations, one of which was novel. This represents the first genetically confirmed KIN case in East Asia involving a novel FAN1 mutation.

A 34-year-old previously healthy Japanese man was referred for progressive renal dysfunction. Four years earlier, his serum creatinine was 1.1 mg/dL; after working in Mexico in the automotive industry, it rose to 1.3 mg/dL with an eGFR based on cystatin C of 76 mL/min/1.73 m². He was born to nonconsanguineous healthy parents with no family history of kidney disease. During his stay abroad, he had a one-week fever treated with antipyretics, without hematuria or edema, and denied toxic exposures or sexual activity. Physical examination was unremarkable. Laboratory tests, kidney biopsy, and targeted sequencing of the FAN1 gene were performed. To assess the functional consequence of the novel FAN1 frameshift variant, wild-type and mutant FAN1 plasmids were transfected into HEK293 cells, and protein expression was evaluated by Western blot (WB) with or without the proteasome inhibitor MG132.

Urinalysis showed no proteinuria or hematuria. Antinuclear antibody, anti-dsDNA antibody, MPO-ANCA, PR3-ANCA, and anti-GBM antibody were negative. Tests for HIV, HTLV-1, CMV, and EBV were also negative. Renal biopsy showed tubular epithelial cells with markedly enlarged, irregular nuclei and ground-glass chromatin, whereas glomeruli were preserved. Immunostaining for SV40, CMV, HSV-1/2, EBER, and adenovirus was negative; Ki-67, a proliferation marker reported to be positive in enlarged nuclei of FAN1 knockout mice was focally positive in enlarged nuclei. Targeted sequencing identified a heterozygous frameshift variant, p.Lys478Ilefs38, unreported in any databases and absent in his mother. Next generation sequencing detected an additional rare frameshift variant, p.Gly663Ilefs54, previously linked to KIN. When the novel variant was overexpressed in HEK293 cells, the mutant protein was undetectable under normal conditions, whereas wild-type FAN1 was robustly expressed. Upon treatment with MG132, the mutant protein became detectable.

We report the first East Asian case of sporadic KIN caused by compound heterozygous FAN1 frameshift mutations, including a novel pathogenic variant (p.Lys478Ilefs*38). Renal biopsy showed typical KIN features, and immunostaining findings excluded viral cytopathy. WB analysis demonstrated that the novel FAN1 mutation is unstable and rapidly degraded via the ubiquitin–proteasome pathway. Taken together with the genetic findings, these results enabled a definitive diagnosis of KIN due to compound heterozygous FAN1 mutations. Recognition of tubular karyomegaly in chronic interstitial nephritis without drug exposure or viral infection should prompt consideration of KIN. This case emphasizes the diagnostic value of integrating pathological and genetic, and biochemical assessments, enabling accurate diagnosis, prognostication, and genetic counseling.