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Lookup NU author(s): Professor John SayerORCiD, Dr Juliana Arcila GalvisORCiD
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© 2025 International Society of NephrologyIntroduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a common monogenic kidney disease leading to kidney failure usually during mid adulthood. It is due to pathogenic variants in at least five genes. However, despite thorough screening of UMOD, MUC1, REN, HNF1B and SEC61A1, 25 to 50% of families remain without molecular diagnosis. Methods: Here, we investigated a cohort of 203 families with ADTK, as well as sporadic cases of kidney disease of unknown etiology and cases of chronic kidney disease stage 5 from the Genomics England 100,000 Genomes Project. Expression of JAG1 in kidney and/or urinary epithelial cell (UREC) lines from patients carrying a pathogenic JAG1 variant associated with isolated ADTKD was studied using immunolabelling, Western blotting, targeted RNA-seq and quantitative RT-PCR. Endoplasmic reticulum (ER) stress was tested by analyzing ER protein BiP expression levels in URECs. Results: A pathogenic or likely pathogenic variant in JAG1, the gene associated with Alagille syndrome, was identified in three large families with unsolved ADTKD, and additional rare variants were identified in sporadic cases. In two of the families, the diagnosis of Alagille syndrome was further established in one infant in the fourth or fifth generation; however, none of the 23 adult patients affected with isolated kidney failure (and tubulointerstitial nephritis in individuals with available kidney biopsy) had overt sign of liver, bile duct, heart, eye, or skeletal defect. JAG1 expression studies as well as ER stress analysis suggests that, despite a noteworthy expression of the JAG1-mutated RNAs, the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function. Conclusions: JAG1 pathogenic variants can be associated with isolated tubulointerstitial nephropathy which, according to the KDIGO guidelines, should be classified as ADTKD-JAG1 when JAG1 variants lead to isolated chronic kidney disease that fulfills the criteria for ADTKD.
Author(s): Menguy L, Hudier L, Zaidan M, Knebelmann B, Sayer JA, Arcila-Galvis J, Arondel C, Hummel A, Dorval G, Moriniere V, Fula-Pitu L, Guerrera C, Buob D, Rabeyrin M, Marijon P, Jean-Marcais N, Fournier C, Duong Van Huyen J-P, Antignac C, Saunier S, Heidet L
Publication type: Article
Publication status: Published
Journal: Kidney International
Year: 2025
Pages: epub ahead of print
Online publication date: 06/10/2025
Acceptance date: 22/08/2025
ISSN (print): 0085-2538
ISSN (electronic): 1523-1755
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.kint.2025.08.033
DOI: 10.1016/j.kint.2025.08.033
PubMed id: 41061854
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