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Pkhd1cyli/cyli mice have altered renal Pkhd1 mRNA processing and hormonally sensitive liver disease
Chaozhe Yang1, Naoe Harafuji1, Ljubica Caldovic2,3
1Center for Translational Research, Children's National Research Institute, Washington, DC, 20010, USA.
Insights
A new mouse model with a Pkhd1 gene mutation develops cystic liver disease but not kidney disease. This suggests ribosomal frameshifting may protect the kidneys by allowing partial protein production, explaining differences from human ARPKD.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Autosomal-recessive polycystic kidney disease (ARPKD) is a severe hereditary disorder affecting the liver and kidneys, often leading to early mortality.
- Mutations in the PKHD1 gene, encoding fibrocystin/polyductin complex (FPC), cause ARPKD.
- Existing mouse models with Pkhd1 gene disruptions do not fully replicate the renal phenotype of human ARPKD.
Purpose of the Study:
- To characterize a spontaneous Pkhd1 mutation in mice that causes a hepato-renal fibrocystic disorder.
- To investigate the molecular mechanisms underlying the observed phenotype, particularly the lack of renal disease despite liver pathology.
- To explore species-specific differences in Pkhd1 gene expression and its impact on disease presentation.
Main Methods:
- Characterization of a spontaneous recessive Pkhd1 mutation in mice, designated Pkhd1^cyli/cyli.
- Genetic mapping of the mutation to Chromosome 1 and identification of an insertion/deletion causing a frameshift in Pkhd1 exon 48.
- Analysis of Pkhd1 mRNA expression in liver and kidney tissues of mutant and wild-type mice.
- Investigation of potential mechanisms like nonsense-mediated decay (NMD) and ribosomal frameshifting.
Main Results:
- Pkhd1^cyli/cyli mice exhibit severe cystic liver disease (cyli) but no renal disease.
- The mutation causes a frameshift in Pkhd1 exon 48, predicted to result in a premature termination codon.
- Reduced Pkhd1 mRNA levels were observed in both liver and kidney tissues of cyli mice compared to wild-type.
- Alternatively spliced Pkhd1 transcripts containing exon 48 were detected in cyli kidneys, suggesting escape from NMD.
- An AAAAAT motif upstream of the mutation may facilitate ribosomal frameshifting, potentially enabling FPC production for renoprotection.
Conclusions:
- The Pkhd1^cyli/cyli mouse model presents a distinct hepato-biliary phenotype without renal involvement, differing from classic ARPKD.
- Ribosomal frameshifting is a potential mechanism allowing Pkhd1 mRNA to escape NMD, leading to sufficient FPC for kidney protection.
- Species-specific mechanisms, such as ribosomal frameshifting, may explain the discrepancies in renal phenotypes between Pkhd1 mutant mice and human ARPKD patients.
Abstract:
Autosomal-recessive polycystic kidney disease (ARPKD; MIM #263200) is a severe, hereditary, hepato-renal fibrocystic disorder that causes early childhood morbidity and mortality. Mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which encodes the protein fibrocystin/polyductin complex (FPC), cause all typical forms of ARPKD. Several mouse lines carrying diverse, genetically engineered disruptions in the orthologous Pkhd1 gene have been generated, but none expresses the classic ARPKD renal phenotype. In the current study, we characterized a spontaneous mouse Pkhd1 mutation that is transmitted as a recessive trait and causes cysticliver (cyli), similar to the hepato-biliary disease in ARPKD, but which is exacerbated by age, sex, and parity. We mapped the mutation to Chromosome 1 and determined that an insertion/deletion mutation causes a frameshift within Pkhd1 exon 48, which is predicted to result in a premature termination codon (UGA). Pkhd1cyli/cyli (cyli) mice exhibit a severe liver pathology but lack renal disease. Further analysis revealed that several alternatively spliced Pkhd1 mRNA, all containing exon 48, were expressed in cyli kidneys, but in lower abundance than in wild-type kidneys, suggesting that these transcripts escaped from nonsense-mediated decay (NMD). We identified an AAAAAT motif in exon 48 upstream of the cyli mutation which could enable ribosomal frameshifting, thus potentially allowing production of sufficient amounts of FPC for renoprotection. This mechanism, expressed in a species-specific fashion, may help explain the disparities in the renal phenotype observed between Pkhd1 mutant mice and patients with PKHD1-related disease. KEY MESSAGES: The Pkhd1cyli/cyli mouse expresses cystic liver disease, but no kidney phenotype. Pkhd1 mRNA expression is decreased in cyli liver and kidneys compared to wild-type. Ribosomal frameshifting may be responsible for Pkhd1 mRNA escape from NMD. Pkhd1 mRNA escape from NMD could contribute to the absent kidney phenotype.
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