Heterozygous truncating variants in BICC1 are a novel cause of autosomal-dominant tubulointerstitial kidney disease
Year: 2026
Type: preprint
Study design: Observational Study
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.
Source: medRxiv
Authors: Naomi Eylath, Kendrah O. Kidd, Piper Alyea-Herman, Julia Meyersiek, Dan A. Colombo, Helmut G. Rennke, Ava J. Guleserian, Victoria W. Adams, Giada Bianchi, Arnaud Maillard, Stanislas Faguer, Claudia Izzi, Carsten Bergmann, Stewart Lecker, Megan E Astley, Abbigail Taylor, Lauren Martin, Sydney Means, Antonio Sanchez, Nelson Weller, Kateřina Hodaňová, Tereza Kmochová, Viktor Stránecký, Hana Hartmannová, Klára Svojšová, Jakub Sikora, Lea Pavlovičová, Hana Yang, Peter C. Harris, Stanislav Kmoch, Anthony J. Bleyer, Martina Živná, Peter G. Czarnecki
Institutions: Beth Israel Deaconess Medical Center, Harvard University, Charles University, Wake Forest University Health Sciences, Wake Forest University, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Louis, Université Toulouse III - Paul Sabatier, Inserm, Centre Hospitalier Universitaire de Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, University of Brescia, Amsterdam UMC Location University of Amsterdam, Amsterdam Public Health, General University Hospital in Prague, Institute of Clinical and Experimental Medicine, Mayo Clinic
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204115315
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