Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
AuthorMuggenthaler, Martina M. A.
Hasan, S. Naimul
Cross, Harold E.
Harlalka, Gaurav V.
Patton, Michael A.
Behr, Elijah R.
Baple, Emma L.
Alkuraya, Fowzan S.
Crosby, Andrew H.
Chioza, Barry A.
AffiliationUniv Arizona, Coll Med, Dept Ophthalmol
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationMutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice 2017, 13 (1):e1006470 PLOS Genetics
Rights© 2017 Muggenthaler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
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AbstractOrofacial 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.
NoteOpen Access Journal.
VersionFinal published version
SponsorsMedical Research Council UK [MR/J011673/1, G1002279]; Canadian Institutes of Health Research [MP-89873]; King Abdulaziz City for Science and Technology [13-BI01113-20]; Manitoba Health Research Council; Manitoba Institute of Child Health studentship