title: Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.
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.
authors.affiliation: RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Martina M A
authors.initials: MM
authors.lastname: Muggenthaler
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Biswajit
authors.identifier: http://orcid.org/0000-0003-0203-8072
authors.initials: B
authors.lastname: Chowdhury
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: S Naimul
authors.initials: SN
authors.lastname: Hasan
authors.affiliation: Department of Ophthalmology, University of Arizona College of Medicine, Tucson, Arizona, United States of America.
authors.forename: Harold E
authors.identifier: http://orcid.org/0000-0002-3073-0085
authors.initials: HE
authors.lastname: Cross
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Mark
authors.affiliation: RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Gaurav V
authors.initials: GV
authors.lastname: Harlalka
authors.affiliation: RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter, United Kingdom.|Genetics Research Centre, St George's University London, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Miho
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Cardiovascular Sciences Research Centre, St George's University of London, London, United Kingdom.
authors.forename: Elijah R
authors.identifier: http://orcid.org/0000-0002-8731-2853
authors.initials: ER
authors.lastname: Behr
authors.affiliation: Cardiovascular Sciences Research Centre, St George's University of London, London, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Pediatric Cardiology, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Kenneth
authors.identifier: http://orcid.org/0000-0002-4556-8439
authors.initials: K
authors.lastname: Zahka
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Otolaryngology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Blakley
authors.affiliation: Department of Small Animal and Materials Imaging Facility, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: Jackson
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lees
authors.affiliation: Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.|Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Vernon
authors.initials: V
authors.lastname: Dolinsky
authors.affiliation: Windows of Hope Genetic Information Centre, Holmes County, Ohio, United States of America.
authors.forename: Leroy
authors.initials: L
authors.lastname: Cross
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.affiliation: Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Salter
authors.affiliation: RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baple
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.identifier: http://orcid.org/0000-0003-4158-341X
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.|Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.|Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
authors.forename: Barbara
authors.identifier: http://orcid.org/0000-0003-4719-6779
authors.initials: B
authors.lastname: Triggs-Raine
authors.affiliation: RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Barry A
authors.identifier: http://orcid.org/0000-0002-3546-1726
authors.initials: BA
authors.lastname: Chioza
mesh_terms: D000293:Adolescent; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D003310:Cor Triatriatum / Q000235:genetics* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D013577:Syndrome
chemical_list: D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C473096:Hyal2 protein, human; C469221:Hyal2 protein, mouse; D006821:Hyaluronoglucosaminidase