New discovery on genetic mutation that leads to cleft lip and palate and heart defects

New discovery on genetic mutation that leads to cleft lip and palate and heart defects

The lip forms between the fourth and seventh weeks of pregnancy. As a baby develops during pregnancy, the body tissue and special cells from each side of the head grow toward the center of the face and join together to make the face. This joining of tissue forms the facial features, like the lips and mouth. A cleft lip happens if the tissue that makes up the lip does not join completely before birth. This results in an opening in the upper lip. The opening in the lip can be a small slit or it can be a large opening that goes through the lip into the nose. A cleft lip can be on one or both sides of the lip or in the middle of the lip, which occurs very rarely.

cleft-lipChildren with a cleft lip also can have a cleft palate. A cleft palate happens if the tissue that makes up the roof of the mouth does not join together completely during pregnancy. For some babies, both the front and back parts of the palate are open. For other babies, only part of the palate is open.

According to the reports of Centers for Disease Control and Prevention (CDC) approximately 2,650 babies are born with a cleft palate every year, and another 4,440 with a cleft lip. Many of the babies affected also have speech impediments and experience difficulties while feeding. Sometimes hearing and vision impairment, or even heart defects, can accompany CLP. They have to undergo several operations to correct the orofacial cleft.

While these orofacial birth defects are common, their cause remains largely unknown. The reason for the genetic changes are said to be the mother’s diet or medication but the exact genetic mechanism was not fully understood.

A team of international researchers from the United Kingdom, Canada, Saudi Arabia, and the U.S set out to investigate the genetic mutations behind CLP and their accompanying heart defects.

Recently ,the team published their research paper in the journal PLOS Genetics .

Clinical studies and genetic mapping

The team, led by Martina Muggenthaler from the University of Exeter in the U.K., examined people with CLP from Amish and Northern Saudi Arabian families.

They identified five Amish children between 4-16 years old with syndromic CLP, and two children aged 7 and 12 years from an Arabic family.

Genetic mapping was done by the researchers to find the chromosomal location of the gene responsible for the disease. They did the a genome-wide single nucleotide polymorphism (SNP) study as the SNPs are the most common form of variation in people’s DNA, which often acts as biological markers that help scientists to locate disease genes.

Further the team undertook a whole exon sequence analysis of a single individual with CLP in order to identify the mutation causing the disease.

After adjusting for various factors such as SNP call quality and population frequency, the team found only one pathogenic variant in the HYAL2 gene.

HYAL2 gene and the mutation

The HYAL2 gene encodes hyaluronidase 2, an enzyme responsible for degrading hyaluronan (also known as hyaluronic acid).

Hyaluronan is a carbohydrate polymer usually found in connective tissue and the hard palate.

Researchers performed enzyme assays, which revealed that the mutations reduced the levels of the HYAL2 protein. This, in turn, inhibited the metabolism of hyaluronic acid.

Hyaluronan is found in the connective tissue of many parts in the body, including the heart, the researchers hypothesized that mutations in the HYAL2 gene would cause CLP and heart defects in mice.

Based on further experiments – including histological studies – on mice that lacked the HYAL2 protein studies, they discovered under development in the mice bones, as well as failed fusion of the palate tissue.

Further studies found cor triatriatum sinister (a common heart defect that accompanies CLP, in which the heart grows a third atrial chamber) in 50 percent of the mice lacking HYAL2.

The research by Muggenthaler and team shows the importance of hyaluronan in the development of the palate and heart.

“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,” says co-author Prof. Andrew Crosby, from the University of Exeter.

Co-author Dr. Emma Baple, of the paper also from the University of Exeter, adds: “It also provides the first molecular cause of the heart defect cor triatriatrum sinister.”

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