Kidney Week

Abstract: FR-PO0072

Molecular Architecture of Fibrocystin and Loss-of-Function Variants Implicated in ARPKD

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Pillai, Joshua, Boston Children's Hospital, Boston, Massachusetts, United States

Joshua Pillai

• Puntambekar, Sidhant N., Boston Children's Hospital, Boston, Massachusetts, United States

Sidhant N. Puntambekar

• Onuchic-Whitford, Ana C., Boston Children's Hospital, Boston, Massachusetts, United States

Ana C. Onuchic-Whitford, MD

• Ferreira, Frederico Moraes, Universidade de Sao Paulo Faculdade de Medicina, São Paulo, SP, Brazil

Frederico Moraes Ferreira, MS, PhD

• Onuchic, Luiz F., Universidade de Sao Paulo Faculdade de Medicina, São Paulo, SP, Brazil

Luiz F. Onuchic, MD, PhD

• Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

• Sayer, John Andrew, Newcastle University, Newcastle upon Tyne, England, United Kingdom

John Andrew Sayer, MBChB, PhD

Background

Fibrocystin/polyductin is a large single-pass transmembrane glycoprotein involved in tubulogenesis and maintenance of the epithelium, where pathogenic variants in its encoding gene PKHD1cause autosomal recessive polycystic kidney disease (ARPKD). While enormous experimental efforts have been taken to characterize proteins involved in autosomal dominant PKD, the structural and molecular basis of fibrocystin has lagged behind with no known mechanistic models.

Methods

We refined the domain architecture of fibrocystin and described the molecular effects of numerous PKHD1 variants with founder effects. Furthermore, we sought to use this biophysical data to resolve genotype-phenotype correlations independently validated against clinical outcome data from 304 ARPKD patients.

Results

We show that missense variants affecting amino acids 709-1837 are often exposed and correlate with lower rates of kidney failure, where the p.R1624W allele is a major contributor. Additionally, we demonstrate that missense variants affecting amino acids 2625-4074 have a molecular effect equivalent to null loss-of-function variants with severe hepatic complications and portal hypertension, which can be rescued when in compound heterozygosity with a variant in amino acids 1838-2624.

Conclusion

We advance understanding of the structural architecture of fibrocystin and resolve long-standing genotype-phenotype correlations, thereby laying the clinical foundation for improved diagnostics and potential therapeutic development for ARPKD.