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

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, w...

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Autores principales: Muggenthaler, Martina M. A., Chowdhury, Biswajit, Hasan, S. Naimul, Cross, Harold E., Mark, Brian, Harlalka, Gaurav V., Patton, Michael A., Ishida, Miho, Behr, Elijah R., Sharma, Sanjay, Zahka, Kenneth, Faqeih, Eissa, Blakley, Brian, Jackson, Mike, Lees, Melissa, Dolinsky, Vernon, Cross, Leroy, Stanier, Philip, Salter, Claire, Baple, Emma L., Alkuraya, Fowzan S., Crosby, Andrew H., Triggs-Raine, Barbara, Chioza, Barry A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5230738/
https://www.ncbi.nlm.nih.gov/pubmed/28081210
http://dx.doi.org/10.1371/journal.pgen.1006470
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author Muggenthaler, Martina M. A.
Chowdhury, Biswajit
Hasan, S. Naimul
Cross, Harold E.
Mark, Brian
Harlalka, Gaurav V.
Patton, Michael A.
Ishida, Miho
Behr, Elijah R.
Sharma, Sanjay
Zahka, Kenneth
Faqeih, Eissa
Blakley, Brian
Jackson, Mike
Lees, Melissa
Dolinsky, Vernon
Cross, Leroy
Stanier, Philip
Salter, Claire
Baple, Emma L.
Alkuraya, Fowzan S.
Crosby, Andrew H.
Triggs-Raine, Barbara
Chioza, Barry A.
author_facet Muggenthaler, Martina M. A.
Chowdhury, Biswajit
Hasan, S. Naimul
Cross, Harold E.
Mark, Brian
Harlalka, Gaurav V.
Patton, Michael A.
Ishida, Miho
Behr, Elijah R.
Sharma, Sanjay
Zahka, Kenneth
Faqeih, Eissa
Blakley, Brian
Jackson, Mike
Lees, Melissa
Dolinsky, Vernon
Cross, Leroy
Stanier, Philip
Salter, Claire
Baple, Emma L.
Alkuraya, Fowzan S.
Crosby, Andrew H.
Triggs-Raine, Barbara
Chioza, Barry A.
author_sort Muggenthaler, Martina M. A.
collection PubMed
description 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.
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spelling pubmed-52307382017-01-31 Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice Muggenthaler, Martina M. A. Chowdhury, Biswajit Hasan, S. Naimul Cross, Harold E. Mark, Brian Harlalka, Gaurav V. Patton, Michael A. Ishida, Miho Behr, Elijah R. Sharma, Sanjay Zahka, Kenneth Faqeih, Eissa Blakley, Brian Jackson, Mike Lees, Melissa Dolinsky, Vernon Cross, Leroy Stanier, Philip Salter, Claire Baple, Emma L. Alkuraya, Fowzan S. Crosby, Andrew H. Triggs-Raine, Barbara Chioza, Barry A. PLoS Genet Research Article 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. Public Library of Science 2017-01-12 /pmc/articles/PMC5230738/ /pubmed/28081210 http://dx.doi.org/10.1371/journal.pgen.1006470 Text en © 2017 Muggenthaler et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Muggenthaler, Martina M. A.
Chowdhury, Biswajit
Hasan, S. Naimul
Cross, Harold E.
Mark, Brian
Harlalka, Gaurav V.
Patton, Michael A.
Ishida, Miho
Behr, Elijah R.
Sharma, Sanjay
Zahka, Kenneth
Faqeih, Eissa
Blakley, Brian
Jackson, Mike
Lees, Melissa
Dolinsky, Vernon
Cross, Leroy
Stanier, Philip
Salter, Claire
Baple, Emma L.
Alkuraya, Fowzan S.
Crosby, Andrew H.
Triggs-Raine, Barbara
Chioza, Barry A.
Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
title Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
title_full Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
title_fullStr Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
title_full_unstemmed Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
title_short Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice
title_sort mutations in hyal2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5230738/
https://www.ncbi.nlm.nih.gov/pubmed/28081210
http://dx.doi.org/10.1371/journal.pgen.1006470
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