Cleft lip or palate results from the combined effects of genes and inflammatory risk factors experienced during pregnancy, such as smoking or infections, finds a new study led by UCL researchers.
The study, published in Nature communicationhas revealed for the first time how genetic and environmental factors come together to form a cleft lip or palate in a developing fetus.
Cleft lip, with or without cleft palate, is the most common craniofacial malformation seen at birth, affecting one in 700 live births. It can have devastating consequences for babies and their families, as the babies can have difficulty eating, speaking and hearing, and are at increased risk for ear infections and dental problems.
Senior author Professor Roberto Mayor (UCL Cell & Developmental Biology) said: “It has been known for some time that there is a genetic component to cleft lip and that some environmental factors such as smoking, stress, infections and malnutrition during pregnancy can also increase the risk of a cleft lip. Here we have shown for the first time how these two factors work together and why both genetic and environmental risk factors are necessary for a child to be born with a cleft lip.”
Based at UCL and the University of São Paulo, the researchers studied families carrying mutations in the e-cadherin gene, known to be involved in cleft lip, but noted that not everyone with the mutation develops cleft lip . They reproduced this mutation in mice and frogs, which caused malformations similar to the cleft lip in humans, but only when the mice and frogs carrying the mutation were also exposed to inflammatory environmental factors. The researchers also found similar effects in human stem cells with both the mutation and inflammation.
The e-cadherin protein plays a role in fetal development because neural crest cells — the embryonic stem cells that form facial features — move together to form the face. In normal development, the cells of the neural crest migrate together in two halves, wrapping around the head, before coming together to form the face. This requires e-cadherin to act as a glue between cells. If the two halves of the neural crest cells do not bind together completely, the child will be born with a cleft lip or palate.
The mutation the researchers identified reduces production of the e-cadherin protein, because DNA methylation reduces transcription, but they found that the mutation alone did not lower e-cadherin levels enough to cause cleft lip. It was only when a fetus with the mutation was also exposed to environmental risk factors that cause inflammation throughout the body (including smoking, stress, malnutrition or infections) that DNA methylation increased and e-cadherin levels were too low for the fetus. neural crest cells to bind together to completely form the lip and palate.
First author Dr. Lucas Alvizi (UCL Cell & Developmental Biology) said: “Our study is the first to show in detail how genetic and environmental factors combine to cause a birth defect, while also being a remarkable example of epigenetics, as environmental factors influence the expression of a gene.”
The researchers hope their findings will help develop new treatments or preventative strategies for cleft lip or palate, and clarify the risk factors to help people reduce the chances of their baby developing the condition.
Professor Mayor said: “Testing for this mutation could be a simple part of antenatal care so that if someone carries the mutation they would be advised to take steps to reduce the risk of inflammation that when combined with the genetic factor could result in a cleft lip. In addition to addressing factors such as smoking, prescribing anti-inflammatory drugs may also help pregnant women who are at risk.”
The study was supported by the Sao Paulo Research Foundation, CEPID-FAPESP (Brazil), Medical Research Council, Biotechnology and Biological Sciences Research Council and Wellcome.
Subject of research
Neural crest E-cadherin loss causes cleft lip/palate through epigenetic modulation via pro-inflammatory gene-environment interaction
Article publication date
May 24, 2023