Mutations responsible for cleft palate and related birth defects identified

January 12, 2017

Researchers located a novel gene mutation causing cleft lip and cleft palate defects, which slows the turnover of hyaluronan, an important component of the hard palate. Martina Muggenthaler working with Prof Andrew Crosby, Dr Emma Baple and colleagues at the University of Exeter (United Kingdom), and Biswajit Chowdhury working with Prof Barb Triggs-Raine of the University of Manitoba (Canada), report these findings January 12th, 2017 in PLOS Genetics.

Cleft lip and cleft palate (CLP) are among the most common birth defects, but the genetics underlying these conditions are poorly understood. By studying individuals with syndromic CLP from Amish and Northern Saudi Arabian families, the researchers identified the responsible mutations. Syndromic CLP is accompanied by other congenital defects such as hearing and vision problems, extra toes or fingers or heart anomalies such as cor triatriatum sinister, where the heart develops a third atrial chamber on the left side. The collaborative team mapped the condition to mutations in the HYAL2 gene, which encodes an enzyme that breaks down hyaluronan, a carbohydrate polymer found widely in connective tissue, and in the hard palate. Enzyme assays showed that the mutations reduced HYAL2 protein levels in the tissues, which likely inhibited hyaluronan turnover, ultimately impacting development of the palate and other body parts.

"This finding is important as it highlights a new molecular cause for orofacial clefting which is likely to be relevant to other as yet unidentified genetic causes of the condition", said Professor Crosby. "It also provides the first molecular cause of the heart defect cor tritriatrium sinister", added Dr Baple.

Further experiments using mice that lack HYAL2 showed that the mice develop defects similar to human syndromic CLP, including cor triatriatum sinister.

Furthermore, the findings illustrate the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development. A better understanding of the factors contributing to these anomalies may contribute to the development of new treatments for these common birth defects, such as hymecromone, a drug approved in many parts of the world that blocks hyaluronan synthesis.
In your coverage please use this URL to provide access to the freely available article in PLOS Genetics:

Citation: Muggenthaler MMA, Chowdhury B, Hasan SN, Cross HE, Mark B, Harlalka GV, et al. (2016) Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice. PLoS Genet 12(12): e1006470. doi:10.1371/journal.pgen.1006470

Funding: This work was funded by the Medical Research Council UK, MMAM - Fellowship MR/J011673/1, AHC - grant G1002279), the Canadian Institutes of Health Research, BTR - grant MP-89873), the King Abdulaziz City for Science and Technology, 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.Competing Interests: The authors have declared that no competing interests exist.


Related Cleft Palate Articles from Brightsurf:

For children with cleft lip and palate, no major psychological impact of repeated surgeries
Children born with cleft lip and cleft palate (CLP) commonly undergo multiple surgical procedures between infancy and adolescence.

Children born with a cleft lip unlikely to be genetically inclined to do poorly at school
New research has found that children born with a cleft lip, either with or without a cleft palate, are not likely to be genetically predisposed to do less well at school than their peers.

Skin and non-adhesive cells found to play pivotal role in the formation of fin
Human fingers are sculpted from a primitive pad-like structure during embryonic development.

Speech impairment in five-year-old international adoptees with cleft palate
In a group of internationally adopted children with cleft lip and/or palate, speech at age five is impaired compared to a corresponding group of children born in Sweden, a study shows.

Variation in the shape of speech organs influences language evolution
Why do speech sounds vary across languages? Does the shape of our speech organs play a role?

The mystery behind cleft palate and lips: Study shines a light on genetic factors
Researchers found more than 100 new genes that could lead to the development of cleft lip and palates.

Salamanders chew with their palate
'According to the textbooks, amphibians swallow their prey whole, but we have been able to refute this,' says Dr.

New technique uses umbilical cord stem cells for early repair of cleft palate
A technique using umbilical cord blood stem cells could be a promising new approach for repair of cleft palate in infants, reports a paper in The Journal of Craniofacial Surgery, published in the Lippincott portfolio by Wolters Kluwer.

Novel genome-wide association study risk loci for nonsyndromic orofacial clefts
At the 96th General Session of the International Association for Dental Research (IADR), held in conjunction with the IADR Pan European Regional (PER) Congress, Azeez Butali, University of Iowa, Iowa City, USA, gave an oral presentation titled 'Novel Genome-wide Association Study Risk Loci for Nonsyndromic Orofacial Clefts.'

In the gaping mouth of ancient crocodiles
A new study by a team of international experts, led by University of Witwatersrand PhD candidate Kathleen Dollman and Professor Jonah Choiniere published today in the American Museum Novitates, endeavoured to further explore the mouth of one of the earliest occurring and least understood groups of crocodilians, the shartegosuchids.

Read More: Cleft Palate News and Cleft Palate Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to