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Mutations in the polycystic kidney and hepatic disease 1 (\n                      <jats:italic>PKHD1<\/jats:italic>\n                      ) 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\n                      <jats:italic>Pkhd1<\/jats:italic>\n                      gene have been generated, but none expresses the classic ARPKD renal phenotype. In the current study, we characterized a spontaneous mouse\n                      <jats:italic>Pkhd1<\/jats:italic>\n                      mutation that is transmitted as a recessive trait and causes\u00a0cysticliver (\n                      <jats:italic>cyli<\/jats:italic>\n                      ), 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\n                      <jats:italic>Pkhd1<\/jats:italic>\n                      exon 48, which is predicted to result in a premature termination codon (UGA).\n                      <jats:italic>Pkhd1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>cyli\/cyli<\/jats:italic>\n                      <\/jats:sup>\n                      (\n                      <jats:italic>cyli<\/jats:italic>\n                      ) mice exhibit a severe liver pathology but lack renal disease. Further analysis revealed that several alternatively spliced\n                      <jats:italic>Pkhd1<\/jats:italic>\n                      mRNA, all containing exon 48, were expressed in\n                      <jats:italic>cyli<\/jats:italic>\n                      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\n                      <jats:italic>cyli<\/jats:italic>\n                      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\n                      <jats:italic>Pkhd1<\/jats:italic>\n                      mutant mice and patients with\n                      <jats:italic>PKHD1<\/jats:italic>\n                      -related disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            The\n                            <jats:italic>Pkhd1<\/jats:italic>\n                            <jats:sup>\n                              <jats:italic>cyli\/cyli<\/jats:italic>\n                            <\/jats:sup>\n                            \u00a0mouse expresses cystic liver disease, but no kidney phenotype.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>Pkhd1<\/jats:italic>\n                            mRNA expression is decreased in\n                            <jats:italic>cyli<\/jats:italic>\n                            liver and kidneys compared to wild-type.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Ribosomal frameshifting may be responsible for\n                            <jats:italic>Pkhd1<\/jats:italic>\n                            mRNA escape from NMD.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>Pkhd1<\/jats:italic>\n                            mRNA escape from NMD could contribute to the absent kidney phenotype.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00109-023-02351-2","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T05:01:47Z","timestamp":1692162107000},"page":"1141-1151","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pkhd1cyli\/cyli mice have altered renal Pkhd1 mRNA processing and hormonally sensitive liver disease"],"prefix":"10.1007","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5388-7173","authenticated-orcid":false,"given":"Chaozhe","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7741-4549","authenticated-orcid":false,"given":"Naoe","family":"Harafuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-5585","authenticated-orcid":false,"given":"Ljubica","family":"Caldovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5055-1229","authenticated-orcid":false,"given":"Weiying","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravindra","family":"Boddu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5589-4652","authenticated-orcid":false,"given":"Surajit","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0507-2532","authenticated-orcid":false,"given":"Hayk","family":"Barseghyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2330-5427","authenticated-orcid":false,"given":"Heather","family":"Gordish-Dressman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oded","family":"Foreman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6635-7569","authenticated-orcid":false,"given":"Zsuzsa","family":"Bebok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva 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