A preclinical pig model of Angelman syndrome mirrors the early developmental trajectory of the human condition

• 成果类型: Article
• 署名作者: Myers, Luke S.; Christian, Sarah G.; Simpson, Sean; Sper, Renan; Taylor, Clint; Montes, Laura; Jepp, Thomas B. C.; Ramos, Daniela; Schuller, Livia; Konganti, Kranti; Friedeck, Wade; Habib, Ozair; Hodge, McKaela; Taylor, Alasdair J.; Coffell, Ashley; Schlafer, Annalise; Matt, Morgan; Revell, Bradley; Knight, Carol; Barrena, Cristina C.; Murphy, William J.; Weeber, Edwin J.; Segal, David J.; Anderson, Anne; Nash, Kevin R.; Silvermanj, Jill L.; Piedrahita, Jorge A.; Dindot, Scott V.
• 署名单位: Texas A&M University System; Texas A&M University College Station; University of Surrey; North Carolina State University; North Carolina State University; Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; State University System of Florida; University of South Florida; University of California System; University of California Davis; University of California System; University of California Davis; Baylor College of Medicine; Baylor College of Medicine; University of California System; University of California Davis; Ultragenyx Pharmaceutical Inc.
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11231
• DOI: 10.1073/pnas.2505152122
• 发表日期: 2025-07-29
• 关键词: ubiquitin ligase; sus-scrofa; ube3a; mutations; gene; ube3a/e6-ap; transcript; deficits; protein; GROWTH

摘要

Angelman syndrome is a neurodevelopmental disorder characterized by severe motor and cognitive deficits. It is caused by the loss of the maternally inherited allele of the imprinted ubiquitin-protein ligase E3A (UBE3A) gene. Rodent models of Angelman syndrome do not fully recapitulate all the symptoms associated with the condition and are limited as a preclinical model for therapeutic development. Here, we show that pigs (Sus scrofa) with a maternally inherited deletion of UBE3A (UBE3A-/+) have altered postnatal behaviors, impaired vocalizations, reduced brain growth, motor incoordination, and ataxia. Neonatal UBE3A-/+ pigs exhibited several symptoms observed in infants with Angelman syndrome, including hypotonia, suckling deficits, and failure to thrive. Collectively, these findings are consistent with the pathophysiology and developmental trajectory observed in individuals with Angelman syndrome. We anticipate that this pig model will advance our understanding of the pathophysiology of Angelman syndrome and be used as a preclinical large animal model for therapeutic development.