Kidney Week

Abstract: SA-PO0618

Truncating Mutations in BICC1 Cause Autosomal Dominant Tubulointerstitial Kidney Disease

Session Information

• Monogenic Kidney Diseases: Tubular and Other
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Czarnecki, Peter G., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Peter G. Czarnecki, MD

• Kidd, Kendrah O., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States

Kendrah O. Kidd, PhD

• Eylath, Naomi, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Naomi Eylath

• Zivna, Martina, Univerzita Karlova, Prague, Czechia

Martina Zivna, MS, MSc, PhD

• Hodanova, Katerina, Univerzita Karlova, Prague, Czechia

Katerina Hodanova, PhD

• Kmoch, Stanislav, Univerzita Karlova, Prague, Czechia

Stanislav Kmoch, MS, MSc, PhD

• Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States

Anthony J. Bleyer, MD, MS, FASN

Background

Bicaudal-C is an RNA-binding protein and posttranscriptional regulator of genes involved in kidney development and embryonic pattern formation. Certain loss-of-function variants in the BICC1 gene cause recessive CAKUT- and/or PKD-like phenotypes in humans and mice. Here, we report for the first time novel truncating mutations in the BICC1 gene as a cause of autosomal-dominant tubulointerstitial kidney disease (ADTKD).

Methods

We identified three families with ADTKD, negative for mutations in UMOD, MUC1, REN, HNF1B, and SEC61A1, in whom the ADTKD phenotype segregated with predicted loss-of-function variants in BICC1. We tested interactions of mutated BICC1 with wildtype BICC1 protein and its interaction partners, ANKS3 and ANKS6, by co-immunoprecipitation and western blotting. We further tested the binding of wildtype and mutated BICC1 protein to a model RNA substrate in a luciferase reporter assay.

Results

We identified 3 families with truncating variants, BICC1 c.1495dup (p.Ala499Glyfs*6); c.1997_1978del (p.Val660Glyfs*15) and c.1204C>T (p.Arg402Ter). Of the 10 individuals identified with a BICC1 variant, 8 had CKD, while two individuals age <32 were clinically asymptomatic. Of 9 genetically unaffected individuals, the lowest eGFR was 59 ml/min/1.73m² at age 90. 4 individuals have reached end stage kidney disease (ESKD) at a mean age of 67.0±6.8 years. Age of ESKD is significantly older than in ADTKD-MUC1 (41.9±13.4), ADTKD-UMOD (47.5±11.7) and ADTKD-REN (44.3±11.2), P<0.00001.
In a luciferase reporter assay of BICC1-mediated posttranscriptional gene regulation, all examined BICC1variants exhibited significantly enhanced target gene expression. We further show that mutant BICC1 protein has higher binding affinity to itself in homo-oligomeric interactions, as well as to its binding partner, ANKS6. These findings support the hypothesis of a gain-of-function mechanism of pathogenicity, consistent with a dominant mode of inheritance.

Conclusion

We report the discovery of heterozygous truncating mutations in the BICC1 gene as a novel cause of ADTKD in three families. While the predicted nature of truncating mutations is loss-of-function, we demonstrate unexpected gain-of-function characteristics, potentially explaining why these alleles act in a dominant mode.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025ee2mwhk9