Heterozygous truncating variants in BICC1 are a novel cause of autosomal-dominant tubulointerstitial kidney disease
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Abstract Introduction Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5 , in a Luciferase reporter assay. Results We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6 th to 7 th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action. Translational Statement Novel disease gene discoveries have a high potential for translational impact. Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is reported to occur in 1-2 individuals per 100,000 but is underrecognized and underdiagnosed. Although several genes have been associated with ADTKD, many cases remain genetically unresolved. Our discovery of BICC1 as a novel gene in ADTKD will lead to improved disease recognition, prognostication and counseling. Through its role in gene regulation, BICC1 is a bona fide target for the molecular study of kidney fibrosis and atrophy, a final common pathway in CKD, as well as for the development of future therapies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Heterozygous truncating variants in <i>BICC1</i> are a novel cause of autosomal-dominant tubulointerstitial kidney disease
- Date Crossref
- 23/08/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Beth Israel Deaconess Medical Center pays non établi dans la noticeÉtablissement de santé
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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Charles University pays non établi dans la noticeUniversité ou école supérieure
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Wake Forest University pays non établi dans la noticeUniversité ou école supérieure
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Brigham and Women's Hospital pays non établi dans la noticeÉtablissement de santé
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Dana-Farber Cancer Institute pays non établi dans la noticeStructure de recherche
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Assistance Publique – Hôpitaux de Paris pays non établi dans la noticeÉtablissement de santé
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Hôpital Saint-Louis Service de Génétique Moléculaire Neurovasculaire pays non établi dans la noticeÉtablissement de santé
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Université Toulouse III - Paul Sabatier pays non établi dans la noticeUniversité ou école supérieure
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Inserm pays non établi dans la noticeOrganisme public
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Université Fédérale de Toulouse Midi-Pyrénées pays non établi dans la noticeUniversité ou école supérieure
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Toulouse Mathematics Institute pays non établi dans la noticeStructure de recherche
Beth Israel Deaconess Medical Center, Harvard University et Charles University, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.