New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene

Abstract

Background: Karyomegalic interstitial nephritis (KIN) is a rare disease entity first described by Burry in 1974. The term KIN was introduced by Mihatsch et al. in 1979. KIN is characterized by chronic tubulointerstitial nephritis associated with enlarged tubular epithelial cell nuclei, which leads to a progressive decline of renal function. The prevalence of this disease is less than 1% of all biopsies, and its pathogenesis is unclear. KIN results from mutations in FAN1 (FANCD2/FANCI-Associated Nuclease 1), a gene involved in the DNA damage response pathway, particularly in the kidney. In this study, we report two Tunisian consanguineous families with KIN caused by mutations in the FAN1 gene.

Methods: Direct sequencing of the coding regions and flanking intronic sequences of the FAN1 gene was performed in three affected members. Three prediction programs (Polyphen-2 software, SIFT, and MutationTaster) were used to predict the functional effect of the detected variations.

Results: Two causative frameshift variants in the FAN1 gene were identified in each family: The previously described frameshift mutation c.2616delA (p.Asp873ThrfsTer17) and a novel mutation c.2603delT (p.Leu868ArgfsTer22) classified as "pathogenic" according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Conclusion: To our best knowledge, this is the first Tunisian study involving familial cases of KIN with mutations in the FAN1 gene. We hypothesize that these findings can expand the mutational spectrum of KIN and provide valuable information on the genetic cause of KIN.

Keywords: Chronic tubulointerstitial nephritis; FAN1 gene; Frameshift variants; Karyomegalic interstitial nephritis.

Fig. 1

a Pedigree of the family A, b Pedigree of the family Z

Fig. 2

Renal histology in Patient IV-7 and Patient IV-12 in family A. a Renal biopsy, Masson’s trichroma (magnification × 400). Proximal tubules with giant nuclei, irregular nuclear membrane (Patient IV-7). b Renal biopsy, hematoxylin and eosine stain (magnification × 200). Giant nuclei with irregular nuclear membrane (Patient IV-7). c, d Renal biopsy, electron microscopy. Giant karyomegalic nuclei with irregular nuclear membrane (Patient IV-7). e Renal biopsy, electron microscopy. Giant karyomegalic nuclei of epithelial cells of proximal tubules (Patient IV-12)

Fig. 3

Renal histology in Patient II 3 in family Z. a Renal biopsy, Masson’s trichroma (magnification × 200).Giant nuclei of tubular epithelium. b Renal biopsy, Masson’s trichroma (magnification × 400). Giant nuclei of tubular epithelium, moderately inflammatory interstitial fibrosis. c Renal biopsy. Hematoxylin and eosine stain (magnification × 200). Karyomegalic nephropathy. d Renal biopsy. Masson’strichroma (magnification × 400). Normal glomerulus

Fig. 4

I: Electropherogram showing the mutation c.2616delA found in family A (a, c mutation found in patient IV-2, b, d wildtype). II: Electropherogram showing the mutation c.2603delT found in family Z (a, c wildtype, b, d mutation found in patient II-3)