Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620522
Title:
Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.
Authors:
Muggenthaler, M M A; Chowdhury, B.; Hasan, S. N.; Cross, H. E.; Mark, B.; Harlalka, G. V.; Patton, M. A.; Ishida, M.; Behr, E. R.; Sharma, S.; Zahka, K.; Faqeih, E.; Blakley, B.; Jackson, M.; Lees, M.; Dolinsky, V. W.; Cross, L.; Stanier, P.; Salter, C.; Baple, E. L.; Alkuraya, F. S.; Crosby, Andrew H.; Triggs-Raine, B.; Chioza, B. A.
Abstract:
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.
Citation:
Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice. 2017, 13 (1):e1006470 PLoS Genet.
Publisher:
PLoS
Journal:
PLoS Genetics
Issue Date:
Jan-2017
URI:
http://hdl.handle.net/11287/620522
DOI:
10.1371/journal.pgen.1006470
PubMed ID:
28081210
Additional Links:
http://dx.plos.org/10.1371/journal.pgen.1006470
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1553-7404
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMuggenthaler, M M Aen
dc.contributor.authorChowdhury, B.en
dc.contributor.authorHasan, S. N.en
dc.contributor.authorCross, H. E.en
dc.contributor.authorMark, B.en
dc.contributor.authorHarlalka, G. V.en
dc.contributor.authorPatton, M. A.en
dc.contributor.authorIshida, M.en
dc.contributor.authorBehr, E. R.en
dc.contributor.authorSharma, S.en
dc.contributor.authorZahka, K.en
dc.contributor.authorFaqeih, E.en
dc.contributor.authorBlakley, B.en
dc.contributor.authorJackson, M.en
dc.contributor.authorLees, M.en
dc.contributor.authorDolinsky, V. W.en
dc.contributor.authorCross, L.en
dc.contributor.authorStanier, P.en
dc.contributor.authorSalter, C.en
dc.contributor.authorBaple, E. L.en
dc.contributor.authorAlkuraya, F. S.en
dc.contributor.authorCrosby, Andrew H.en
dc.contributor.authorTriggs-Raine, B.en
dc.contributor.authorChioza, B. A.en
dc.date.accessioned2017-11-21T13:21:26Z-
dc.date.available2017-11-21T13:21:26Z-
dc.date.issued2017-01-
dc.identifier.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 Genet.en
dc.identifier.issn1553-7404-
dc.identifier.pmid28081210-
dc.identifier.doi10.1371/journal.pgen.1006470-
dc.identifier.urihttp://hdl.handle.net/11287/620522-
dc.description.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.en
dc.language.isoenen
dc.publisherPLoSen
dc.relation.urlhttp://dx.plos.org/10.1371/journal.pgen.1006470en
dc.rightsArchived with thanks to PLoS geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subject.meshAdolescent-
dc.subject.meshAnimals-
dc.subject.meshCell Adhesion Molecules-
dc.subject.meshChild-
dc.subject.meshChild, Preschool-
dc.subject.meshCleft Lip-
dc.subject.meshCleft Palate-
dc.subject.meshCor Triatriatum-
dc.subject.meshFemale-
dc.subject.meshGPI-Linked Proteins-
dc.subject.meshHumans-
dc.subject.meshHyaluronoglucosaminidase-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMutation-
dc.subject.meshPedigree-
dc.subject.meshPenetrance-
dc.subject.meshSyndrome-
dc.titleMutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.en
dc.typeJournal Articleen
dc.identifier.journalPLoS Geneticsen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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