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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Body Patterning / genetics*
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Embryo, Nonmammalian / embryology
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Embryo, Nonmammalian / metabolism
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Family Health
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Female
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Gene Expression Regulation, Developmental
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Genes, Recessive
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Heart / embryology
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Heart Defects, Congenital / genetics
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Heterotaxy Syndrome / genetics*
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Humans
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In Situ Hybridization
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Male
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Matrix Metalloproteinases, Secreted / genetics*
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Mice
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Pedigree
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Point Mutation*
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Sequence Analysis, DNA / methods
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Vertebrates / genetics*
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish Proteins / genetics
Substances
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Zebrafish Proteins
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MMP21 protein, human
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Matrix Metalloproteinases, Secreted