Pkhd1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/congenital hepatic fibrosis (CHF), encodes a 4074-amino acid protein called fibrocystin or polyductin. Its function remains unclear, but it is crucial as mutations in PKHD1 lead to ARPKD, a severe hepato-renal fibrocystic disorder causing childhood morbidity and mortality [1,2,3,4,6,7]. Mouse models are valuable for studying Pkhd1 [5].

In the Pkhd1cyli/cyli mouse model, a frameshift mutation in exon 48 leads to a premature termination codon. These mice show severe liver pathology similar to ARPKD, but lack renal disease. Analysis revealed alternative splicing of Pkhd1 mRNA in cyli kidneys, with transcripts containing exon 48 escaping nonsense-mediated decay (NMD), potentially due to an AAAAAT motif enabling ribosomal frameshifting and allowing sufficient production of FPC for renoprotection [5].

In conclusion, Pkhd1 is essential in preventing ARPKD-related hepato-renal fibrocystic disorders. The Pkhd1cyli/cyli mouse model provides insights into the mechanisms underlying the differential renal phenotypes observed between mice and patients with PKHD1-related diseases, highlighting the importance of mRNA processing and potential ribosomal frameshifting in disease manifestation [5].

References:

1. Gunay-Aygun, Meral, Tuchman, Maya, Font-Montgomery, Esperanza, Guay-Woodford, Lisa, Gahl, William A. 2009. PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis. In Molecular genetics and metabolism, 99, 160-73. doi:10.1016/j.ymgme.2009.10.010. https://pubmed.ncbi.nlm.nih.gov/19914852/

2. Bergmann, Carsten, Senderek, Jan, Windelen, Ellen, Büttner, Reinhard, Zerres, Klaus. . Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). In Kidney international, 67, 829-48. doi:. https://pubmed.ncbi.nlm.nih.gov/15698423/

3. Burgmaier, Kathrin, Brinker, Leonie, Erger, Florian, Schaefer, Franz, Liebau, Max Christoph. 2021. Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants. In Kidney international, 100, 650-659. doi:10.1016/j.kint.2021.04.019. https://pubmed.ncbi.nlm.nih.gov/33940108/

4. Bergmann, Carsten, Senderek, Jan, Küpper, Fabian, Büttner, Reinhard, Zerres, Klaus. . PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). In Human mutation, 23, 453-63. doi:. https://pubmed.ncbi.nlm.nih.gov/15108277/

5. Yang, Chaozhe, Harafuji, Naoe, Caldovic, Ljubica, Eicher, Eva M, Guay-Woodford, Lisa M. 2023. Pkhd1cyli/cyli mice have altered renal Pkhd1 mRNA processing and hormonally sensitive liver disease. In Journal of molecular medicine (Berlin, Germany), 101, 1141-1151. doi:10.1007/s00109-023-02351-2. https://pubmed.ncbi.nlm.nih.gov/37584738/

6. Burgmaier, Kathrin, Broekaert, Ilse J, Liebau, Max C. . Autosomal Recessive Polycystic Kidney Disease: Diagnosis, Prognosis, and Management. In Advances in kidney disease and health, 30, 468-476. doi:10.1053/j.akdh.2023.01.005. https://pubmed.ncbi.nlm.nih.gov/38097335/

7. Yang, Hana, Sieben, Cynthia J, Schauer, Rachel S, Harris, Peter C. . Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes. In Advances in kidney disease and health, 30, 397-406. doi:10.1053/j.akdh.2023.04.004. https://pubmed.ncbi.nlm.nih.gov/38097330/