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.

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