{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:41:11Z","timestamp":1788424871464,"version":"build-2803163510"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T00:00:00Z","timestamp":1711152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science and Innovation and European Regional Development Fund","award":["PID PID2022-137238OB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID PID2022-137238OB-I00\/AEI\/10.13039\/501100011033"]}]},{"name":"Spanish Ministry of Science and Innovation and European Regional Development Fund","award":["PID2019-105344RB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2019-105344RB-I00\/AEI\/10.13039\/501100011033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We have generated using CRISPR\/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G&amp;gt;A. This variant creates an alternative 3\u2032 splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.<\/jats:p>","DOI":"10.1093\/hmg\/ddae051","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T20:13:34Z","timestamp":1711224814000},"page":"1074-1089","source":"Crossref","is-referenced-by-count":6,"title":["PAH deficient pathology in humanized c.1066-11G&amp;gt;A phenylketonuria mice"],"prefix":"10.1093","volume":"33","author":[{"given":"Ainhoa","family":"Mart\u00ednez-Pizarro","sequence":"first","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Instituto Universitario de Biolog\u00eda Molecular, UAM, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz), Pedro Rico, 6, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pic\u00f3","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ar\u00edstides","family":"L\u00f3pez-M\u00e1rquez","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Instituto Universitario de Biolog\u00eda Molecular, UAM, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Rodriguez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Montalvo","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Instituto Universitario de Biolog\u00eda Molecular, UAM, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Castro","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz), Pedro Rico, 6, 28029 Madrid, Spain"},{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares (CEDEM), Francisco Tom\u00e1s y Valiente 7, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Ram\u00f3n-Maiques","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain"},{"name":"Instituto de Biomedicina de Valencia (IBV-CSIC), Jaume Roig, 11, 46010 Val\u00e8ncia, Valencia , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Instituto Universitario de Biolog\u00eda Molecular, UAM, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz), Pedro Rico, 6, 28029 Madrid, Spain"},{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares (CEDEM), Francisco Tom\u00e1s y Valiente 7, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 J","family":"Lucas","sequence":"additional","affiliation":[{"name":"Universidad Aut\u00f3noma de Madrid, Nicol\u00e1s Cabrera 1, 28049 Madrid, Spain Centro de Biolog\u00eda Molecular Severo Ochoa UAM-CSIC,"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Av. 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