title: A mouse model of conduction system patterning abnormalities in heterotaxy syndrome.
abstract: Duplication or absence of parts of the specialized cardiac conduction system in patients with heterotaxy syndrome causes significant clinical disease, but the mechanistic basis by which embryonic disruption of left-right patterning alters conduction system patterning in these patients is not well understood. We sought to determine whether a mouse model of X-linked human heterotaxy recapitulates conduction system abnormalities identified in patients with heterotaxy. Cardiac structure and conduction system patterning were evaluated in Zic3 null embryos from e9.5 to e16.5 using genetic and molecular methods. Severe structural abnormalities involving atrial, ventricular, and conotruncal development were associated with a spectrum of disorganized and ambiguous arrangements throughout the conduction system, including the appearance of duplicated structures. The severity and location of conduction system abnormalities correlated with the severity and location of associated structural heart disease and were identifiable at the earliest stages examined. The Zic3 mouse model provides a novel tool to dissect the mechanistic underpinnings of conduction system patterning and dysfunction and its relationship to cardiovascular malformations, making it a promising model to improve understanding and risk assessment in the clinical arena.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Czosek
authors.forename: Allison
authors.initials: A
authors.lastname: Haaning
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D003914:Dextrocardia / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000503:physiopathology; D005865:Gestational Age; D006329:Heart Conduction System / Q000002:abnormalities* / Q000503:physiopathology; D006352:Heart Ventricles / Q000002:abnormalities; D059446:Heterotaxy Syndrome; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012720:Severity of Illness Index; D012849:Sinoatrial Node / Q000002:abnormalities; D012857:Situs Inversus / Q000235:genetics / Q000503:physiopathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C491594:Zic3 protein, mouse