Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.
Public Library of Science
Copyright: © 2017 Muggenthaler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development.
This work was funded by the Medical Research Council UK (http://gtr.rcuk.ac.uk/, MMAM - Fellowship MR/J011673/1, AHC - grant G1002279), the Canadian Institutes of Health Research (http://webapps.cihr-irsc.gc.ca/funding/, BTR – grant MP-89873), the King Abdulaziz City for Science and Technology (http://www.kacst.edu.sa/, FSA – grant 13-BIO1113-20), and a joint Manitoba Health Research Council and Manitoba Institute of Child Health studentship (BC).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Vol. 13, Iss. 1, pp. e1006470 -
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