MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates

  • Nat Genet. 2015 Nov;47(11):1260-3. doi: 10.1038/ng.3376.
Anne Guimier  1  2 ,  George C Gabriel  3 ,  Fanny Bajolle  4 ,  Michael Tsang  3 ,  Hui Liu  5  6 ,  Aaron Noll  7  8 ,  Molly Schwartz  3 ,  Rajae El Malti  5  6 ,  Laurie D Smith  7  8 ,  Nikolai T Klena  3 ,  Gina Jimenez  5  6 ,  Neil A Miller  7  8 ,  Myriam Oufadem  1  2 ,  Anne Moreau de Bellaing  5  6 ,  Hisato Yagi  3 ,  Carol J Saunders  7  8 ,  Candice N Baker  9 ,  Sylvie Di Filippo  10 ,  Kevin A Peterson  9 ,  Isabelle Thiffault  7  8 ,  Christine Bole-Feysot  1  2 ,  Linda D Cooley  7  8 ,  Emily G Farrow  7  8 ,  Cécile Masson  1  2 ,  Patric Schoen  11 ,  Jean-François Deleuze  12 ,  Patrick Nitschké  1  2 ,  Stanislas Lyonnet  1  2  13 ,  Loic de Pontual  1  2 ,  Stephen A Murray  9 ,  Damien Bonnet  2  4 ,  Stephen F Kingsmore  7  8 ,  Jeanne Amiel  1  2  13 ,  Patrice Bouvagnet  5  6 ,  Cecilia W Lo  3 ,  Christopher T Gordon  1  2
Affiliations
  • 1. Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France.
  • 2. Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
  • 3. Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
  • 4. 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.
  • 5. Laboratoire Cardiogénétique, Hospices Civils de Lyon, Bron, France.
  • 6. EA 4173, Université Lyon 1 and Hôpital Nord Ouest, Lyon, France.
  • 7. Center for Pediatric Genomic Medicine, Departments of Pediatrics and Pathology, Children's Mercy-Kansas City, Kansas City, Missouri, USA.
  • 8. University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
  • 9. The Jackson Laboratory, Bar Harbor, Maine, USA.
  • 10. Service de Cardiologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
  • 11. Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
  • 12. Centre National de Génotypage, Institut de Génomique, Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Evry, France.
  • 13. Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
PMID: 26437028 DOI: 10.1038/ng.3376
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.