title: MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates.
abstract: Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Guimier
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Gabriel
authors.affiliation: Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de Référence Malformations Cardiaques Congénitales Complexes (M3C), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Bajolle
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tsang
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Bron, France.|EA 4173, Université Lyon 1 and Hôpital Nord Ouest, Lyon, France.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Noll
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Bron, France.|EA 4173, Université Lyon 1 and Hôpital Nord Ouest, Lyon, France.
authors.forename: Rajae
authors.initials: R
authors.lastname: El Malti
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Smith
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Nikolai T
authors.initials: NT
authors.lastname: Klena
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Bron, France.|EA 4173, Université Lyon 1 and Hôpital Nord Ouest, Lyon, France.
authors.forename: Gina
authors.initials: G
authors.lastname: Jimenez
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Miller
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Oufadem
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Bron, France.|EA 4173, Université Lyon 1 and Hôpital Nord Ouest, Lyon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau de Bellaing
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Hisato
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Saunders
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Candice N
authors.initials: CN
authors.lastname: Baker
authors.affiliation: Service de Cardiologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Di Filippo
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Peterson
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Linda D
authors.initials: LD
authors.lastname: Cooley
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Farrow
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Masson
authors.affiliation: Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
authors.forename: Patric
authors.initials: P
authors.lastname: Schoen
authors.affiliation: Centre National de Génotypage, Institut de Génomique, Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.|Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Loic
authors.initials: L
authors.lastname: de Pontual
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Murray
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.|Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de Référence Malformations Cardiaques Congénitales Complexes (M3C), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.|Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Bron, France.|EA 4173, Université Lyon 1 and Hôpital Nord Ouest, Lyon, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bouvagnet
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Christopher T
authors.identifier: http://orcid.org/0000-0002-9300-8399
authors.initials: CT
authors.lastname: Gordon
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D005192:Family Health; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics; D059446:Heterotaxy Syndrome / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics*; D051379:Mice; D010375:Pedigree; D017354:Point Mutation; D017422:Sequence Analysis, DNA / Q000379:methods; D014714:Vertebrates / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D029961:Zebrafish Proteins; C471969:MMP21 protein, human; D053505:Matrix Metalloproteinases, Secreted