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Pkhd1cyli/cyli mice have altered renal Pkhd1 mRNA processing and hormonally sensitive liver disease
Ist Teil von
Journal of molecular medicine (Berlin, Germany), 2023-09, Vol.101 (9), p.1141-1151
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2023
Link zum Volltext
Quelle
SpringerNature Journals
Beschreibungen/Notizen
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).
Pkhd1
cyli/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
Pkhd1
cyli/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.