title: Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms.
abstract: Atrioventricular septal defects (AVSDs) are a common severe form of congenital heart disease (CHD). In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, in independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia are required for left/right body axis determination and second heart field (SHF) Hedgehog (Hh) signaling, and we find that cilia mutations affect these requirements differentially. Dnah11avc4did not disrupt SHF Hh signaling and caused AVSDs only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1avc6disrupted SHF Hh signaling and caused AVSDs without heterotaxy. We performed unbiased whole-genome SHF transcriptional profiling and found that cilia motility genes were not expressed in the SHF whereas cilia structural and signaling genes were highly expressed. SHF cilia gene expression predicted the phenotypic concordance between AVSDs and heterotaxy in mice and humans with cilia gene mutations. A two-step model of cilia action accurately predicted the AVSD/heterotaxyu phenotypic expression pattern caused by cilia gene mutations. We speculate that cilia gene mutations contribute to both syndromic and non-syndromic AVSDs in humans and provide a model that predicts the phenotypic consequences of specific cilia gene mutations.
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA, imoskowitz@uchicago.edu burnickatureko@uchicago.edu.
authors.forename: Ozanna
authors.initials: O
authors.lastname: Burnicka-Turek
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Steimle
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Felker
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kamp
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Junghun
authors.initials: J
authors.lastname: Kweon
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peterson
authors.affiliation: Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
authors.affiliation: Knight Cardiovascular Institute and Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA and.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Maslen
authors.affiliation: Department of Cardiothoracic Surgery, University of Iowa, Iowa City, IA 52245, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xinan H
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA, imoskowitz@uchicago.edu burnickatureko@uchicago.edu.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
mesh_terms: D000818:Animals; D056444:Axonemal Dyneins / Q000096:biosynthesis / Q000235:genetics*; D019521:Body Patterning / Q000235:genetics; D002923:Cilia / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000633:toxicity; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology; D006343:Heart Septal Defects / Q000235:genetics* / Q000473:pathology; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; C509165:MKS1 protein, human; D011506:Proteins; D056444:Axonemal Dyneins; C465433:DNAH11 protein, human; D005038:Ethylnitrosourea